Bi- and tricyclic indazole-substituted 1,4-dihydropyridine derivatives and uses thereof

ABSTRACT

This invention relates to novel bi- and tricyclic indazole-substituted 1,4-dihydropyridine derivatives having protein tyrosine kinase inhibitory activity, to a process for the manufacture thereof and to the use thereof for the treatment of c-Met-mediated diseases or c-Met-mediated conditions, particularly cancer and other proliferative disorders.

This invention relates to novel bi- and tricyclic indazole-substituted1,4-dihydropyridine derivatives having protein tyrosine kinaseinhibitory activity, to a process for the manufacture thereof and to theuse thereof for the treatment of c-Met-mediated diseases orc-Met-mediated conditions, particularly cancer and other proliferativedisorders.

Cancer is one of the most common widespread diseases. Over 4.4 millionpeople worldwide were diagnosed with breast, colon, ovarian, lung orprostate cancer in 2002, and over 2.5 million people died of thesedevastating diseases (Globocan 2002 Report,http://www-dep.iarc.fr/globocan/downloads.htm). In the United Statesalone, over 1.25 million new cases and over 500 000 deaths from cancerwere predicted in 2005. The majority of these new cases were expected tobe cancers of the colon (˜100 000), lung (˜470 000), breast (˜210 000)and prostate (˜230 000). Both the incidence and prevalence of cancer ispredicted to increase by approximately 15% over the next ten years,reflecting an average growth rate of 1.4% (American Cancer Society,Cancer Facts and Figures 2005;http://www.cancer.org/docroot/STT/content/STT_(—)1x_Cancer_Facts_Figures_(—)2007.asp).

There are many ways how cancers can arise, which is one of the reasonswhy their therapy is difficult. One way is the transformation of cellsby oncoproteins, which arise from normal cellular proteins by geneticmutations, which results in a non-physiological activation of theseproteins. One family of proteins from which a number of oncoproteinsderive are tyrosine kinases (e.g. src kinase) and in particular receptortyrosine kinases (RTKs). In the past two decades, numerous avenues ofresearch have demonstrated the importance of receptor tyrosine kinase(RTK)-mediated signalling in the regulation of mammalian cell growth.Recently, results have been achieved in the clinic with selectivesmall-molecule inhibitors of tyrosine kinases as anti-tumourigenicagents.

The c-Met receptor also is a receptor tyrosine kinase. Its oncogenicpotential was identified in the early 1980s, when a mutated Met wasisolated from a chemically induced human osteosarcoma cell line whichcontained the kinase domain of the Met gene fused to a dimerizationdomain at its N-terminus [C. S. Cooper et al., Nature 311: 29-33(1984)].

The cellular Met protein is a heterodimeric transmembrane proteinsynthesized as a single chain 190 kd precursor [G. A. Rodrigues et al.,Mol. Cell. Biol. 11: 2962-70 (1991)]. The precursor is cleavedintracellularly after amino acid residue 307 to form the 50 kd α-chainand the 145 kd (3-chain, which are connected by disulfide bridges. Theα-chain is entirely extracellular, whereas the β-chain spans the plasmamembrane. The β-chain is composed of an N-terminal sema domain, whichtogether with the α-chain mediates ligand binding. The remainder of theectodomain of the β-chain is composed of a cysteine-rich domain and fourimmunoglobulin domains and is followed by the transmembrane region andthe intracellular domain. The intracellular domain contains ajuxtamembrane domain, the kinase domain and a C-terminal domain, whichmediates the down-stream signalling. Upon ligand binding, a dimerizationof the receptor is induced, and the kinase domain is activated by acascade of tyrosine autophosphorylation steps in the juxtamembraneregion (Y1003), the activation loop of the kinase (Y1234 and Y1235) andthe carboxy-terminal domain (Y1349 and Y1356). Phosphorylated Y1349 andY1356 comprise the multi-substrate docking site for binding adapterproteins necessary for downstream c-Met signalling [C. Ponzetto et al.,Cell 77: 261-71 (1994)]. One of the most crucial substrates for c-Metsignalling is the scaffolding adaptor protein Gabl, which binds toeither Y1349 or Y1356 via an unusual phosphotyrosine binding site(termed mbs: met binding site) which causes a unique prolongedintracellular signal. Another important substrate is the adaptor proteinGrb2. Depending on the cellular context, these adaptors mediate theactivation of various intracellular signal pathways like the onessignalling via ERK/MAPK, PI3K/Akt, Ras, INK, STAT, NFκB and β-catenin.

c-Met is uniquely activated by hepatocyte growth factor (HGF), alsoknown as scatter factor, and its splice variants, which is its onlyknown biologically active ligand [L. Naldini et al., Oncogene 6: 501-4(1991)]. HGF has a distinct structure which reveals similarities toproteinases of the plasminogen family. It is composed of anamino-terminal domain followed by four kringle domains and a serineprotease homology domain, which is not enzymatically active. Similar toc-Met, HGF is synthesized as an inactive single chain precursor(pro-HGF), which is extracellularly cleaved by serine proteases (e.g.plasminogen activators and coagulation factors) and converted into adisulfide-linked active α- and β-chain heterodimer. HGF binds heparansulfate proteoglycans with high affinity, which keeps it mainlyassociated with the extracellular matrix and limits its diffusion.Crystal structure analyses indicate that HGF forms a dimer, which uponbinding to c-Met induces dimerization of the receptor.

HGF is expressed by mesenchymal cells, and its binding to c-Met, whichis widely expressed in particular in epithelial cells, results inpleiotropic effects in a variety of tissues including epithelial,endothelial, neuronal and hematopoetic cells. The effects generallyinclude one or all of the following phenomena: i) stimulation ofmitogenesis; HGF was identified by its mitogenic activity onhepatocytes; ii) stimulation of invasion and migration; in anindependent experimental approach, HGF was identified as scatter factorbased on its induction of cell motility (“scattering”); and iii)stimulation of morphogenesis (tubulogenesis). HGF induces the formationof branched tubules from canine kidney cells in a collagen matrix.Furthermore, evidence from genetically modified mice and from cellculture experiments indicate that c-Met acts as a survival receptor andprotects cells from apoptosis [N. Tomita et al., Circulation 107:1411-1417 (2003); S. Ding et al., Blood 101: 4816-4822 (2003); Q. Zenget al., J. Biol. Chem. 277: 25203-25208 (2002); N. Horiguchi et al.,Oncogene 21: 1791-1799 (2002); A. Bardelli et al., Embo J. 15: 6205-6212(1996); P. Longati et al., Cell Death Differ. 3: 23-28 (1996); E. M.Rosen, Symp. Soc. Exp. Biol. 47: 227-234 (1993)]. The coordinatedexecution of these biological processes by HGF results in a specificgenetic program which is termed as “invasive growth”.

Under normal conditions, c-Met and HGF are essential for embryonicdevelopment in mice, in particular for the development of the placentaand the liver and for the directional migration of myoblasts from thesomites of the limbs. Genetic disruption of the c-Met or HGF genesresults in identical phenotypes which shows their unique interaction.The physiological role of c-Met/HGF in the adult organism is less wellunderstood, but experimental evidence suggests that they are involved inwound healing, tissue regeneration, hemopoiesis and tissue homeostasis.

The identification of the oncoprotein TPR-MET was a first hint thatc-Met may play a role in tumourigenesis. Additional substantial evidenceis derived from a number of different experimental approaches.Overexpression of c-Met or HGF in human and murine cell lines inducestumourigenicity and a metastatic phenotype when expressed in nude mice.Transgenic overexpression of c-Met or HGF induces tumourigenesis inmice.

Most intriguingly, missense mutations of c-Met or mutations whichactivate the receptor have been identified in sporadic and hereditarypapillary kidney carcinomas (HPRC) as well as in other cancer types likelung, gastric, liver, head and neck, ovarian and brain cancers.Significantly, specific c-Met mutations in HPRC families segregate withdisease, forming a causal link between c-Met activation and human cancer[L. Schmidt et al., Nat. Genet. 16: 68-73 (1997); B. Thar et al., Adv.Cancer Res. 75: 163-201 (1998)]. Activation mutations with the strongesttransforming activities are located in the activation loop (D1228N/H andY1230H/D/C) and in the adjacent P+1 loop (M1250T). Additional weakermutations have been found near the catalytic loop and within the A lobeof the kinase domain. Furthermore, some mutations in the juxtamembranedomain of c-Met have been observed in lung tumours which do not directlyactivate the kinase, but rather stabilize the protein by rendering itresistant to ubiquitination and subsequent degradation [M. Kong-Beltranet al., Cancer Res. 66: 283-9 (2006); T. E. Taher et al., J. Immunol.169: 3793-800 (2002); P. Peschard et al., Mol. Cell. 8: 995-1004(2001)]. Interestingly, somatic mutations of c-Met are associated withincreased aggressiveness and extensive metastases in various cancers.While the frequency of germ line and somatic mutations is low (below5%), other major mechanisms have been observed leading to a deregulationof the c-Met signalling, in the absence of mutations, by paracrine orautocrine mechanisms. Paracrine activation has been observed in tumourswhich are derived from mesenchymal cells, like osteosarcomas orrhabdomyosarcomas, which physiologically produce HGF, and inglioblastomas and mamma carcinomas which are of ectodermal origin.

However, the most frequent cases are carcinomas where c-Met isoverexpressed as observed in carcinomas of the colon, pancreas, stomach,breast, prostate, ovary and liver. Overexpression may arise, forexample, by gene amplification as observed in gastric and lung tumourcell lines. Very recently, overexpression of c-Met was detected in lungtumour cell lines which acquired resistance to EGF receptor inhibition[J. A. Engelmann et al., Science 316: 1039-1043 (2007)]. Some epithelialtumours that overexpress c-Met also co-express HGF, resulting in anautocrine c-Met/HGF stimulatory loop and thereby circumventing the needfor stromal cell-derived HGF.

In general, it has been found that aberrant activation of c-Met in humancancer is typically associated with a poor prognosis, regardless of thespecific mechanism [J. G. Christensen et al., Cancer Lett. 225: 1-26(2005)].

In summary, a great number of in vitro and in vivo studies have beenperformed that validate c-Met as an important cancer target, and acomprehensive list can be viewed at http://www.vai.org/met [C.Birchmeier et al., Nat. Rev. Mol. Cell. Biol. 4: 915-25 (2003)]. Severalstrategies have been followed to attenuate aberrant Met signalling inhuman tumours including HGF antagonists and small molecule inhibitors,amongst others. A number of small molecule inhibitors are currently inclinical development, such as ARQ-197 (Arqule), foretinib (XL-880,Exelixis/GSK), and PH-2341066 (Pfizer); they have recently been reviewed[J. J. Cui, Expert Opin. Ther. Patents 17: 1035-45 (2007)].

Lactone-, lactame- or cycloalkanone-annellated4-heteroaryl-1,4-dihydropyridine derivatives that are useful for thetreatment of cardiovascular diseases have been described in, inter al.,EP 0 214 437-A2, EP 0 234 517-A1, EP 0 450 420-A2, EP 0 622 365-A1, EP 0622 366-A1 and EP 0 630 895-A1. Further 4-heteroaryl-1,4-dihydropyridinederivatives containing a fused ring system in 2,3-position and usethereof for the treatment of various diseases have been disclosed in WO00/51986-A1, WO 00/78768-A1, WO 02/10164-A2, WO 2005/025507-A2, WO2006/047537-A1, WO 2006/066011-A2 and WO 2007/051062-A2. Recently,1,4-dihydropyridine-type compounds having c-Met kinase inhibitoryactivity have been described in WO 2008/071451-A1.

The technical problem to be solved according to the present inventionmay therefore be seen in providing alternative compounds having aninhibitory activity on the c-Met kinase, thus offering new therapeuticoptions for the treatment of c-Met-mediated diseases, particularlycancer and other proliferative disorders.

In one aspect, the present invention relates to indazole-substituted1,4-dihydropyridine derivatives of the general formula (I)

wherein

-   A is —C(═O)— or —S(═O)₂—,-   D is —CR^(6A)R^(6B)—, —O— or —NR⁷—, wherein    -   R^(6A), R^(6B) and R⁷ are independently hydrogen or        (C₁-C₄)-alkyl optionally substituted with hydroxy or up to three        fluoro atoms,-   E is —CR^(8A)R^(8B)— or *—CR^(8A)R^(8B)—CR^(8C)R^(8D)—**, wherein    -   * denotes the link to the dihydropyridine ring,    -   ** denotes the link to the D group,    -   and    -   R^(8A), R^(8B), R^(8C) and R^(8D) are independently hydrogen,        fluoro or (C₁-C₄)-alkyl optionally substituted with hydroxy,        (C₁-C₄)-alkoxy, amino, mono-(C₁-C₄)-alkylamino or        di-(C₁-C₄)-alkylamino or up to three fluoro atoms,    -   or    -   R^(8A) and R^(8B) are joined and, taken together with the carbon        atom to which they are attached, form a cyclopropyl or        cyclobutyl ring,-   R¹ is selected from the group consisting of hydrogen, chloro, bromo,    (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl, phenyl, 4- to 7-membered    heterocycloalkyl, 5- to 10-membered heteroaryl and    benzo-1,4-dioxanyl, wherein    -   (i) said (C₃-C₇)-cycloalkyl, phenyl, 4- to 7-membered        heterocycloalkyl and 5- to 10-membered heteroaryl are optionally        substituted with one or two substituents independently selected        from the group consisting of fluoro, chloro, bromo,        difluoromethyl, trifluoromethyl, (C₁-C₄)-alkyl, oxo, hydroxy,        difluoromethoxy, trifluoromethoxy, (C₁-C₄)-alkoxy, amino,        mono-(C₁-C₄)-alkylamino, di-(C₁-C₄)-alkylamino,        (C₃-C₆)-cycloalkyl and 4- to 6-membered heterocycloalkyl,        -   wherein the alkyl groups of said (C₁-C₄)-alkoxy,            mono-(C₁-C₄)-alkylamino and di-(C₁-C₄)-alkylamino            substituents in turn are optionally substituted with hydroxy            or (C₁-C₄)-alkoxy,    -   and    -   (ii) said (C₁-C₆)-alkyl is optionally substituted with one, two        or three substituents independently selected from the group        consisting of fluoro, trifluoromethyl, hydroxy, (C₁-C₄)-alkoxy,        amino, mono-(C₁-C₄)-alkylamino, di-(C₁-C₄)-alkylamino,        (C₃-C₇)-cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl        and 5- to 10-membered heteroaryl,        -   wherein said (C₃-C₇)-cycloalkyl, phenyl, 4- to 7-membered            heterocycloalkyl and 5- to 10-membered heteroaryl            substituents in turn are optionally substituted with one or            two residues independently selected from the group            consisting of fluoro, chloro, bromo, difluoromethyl,            trifluoromethyl, (C₁-C₄)-alkyl, oxo, hydroxy,            difluoromethoxy, trifluoromethoxy, (C₁-C₄)-alkoxy, amino,            mono-(C₁-C₄)-alkylamino and di-(C₁-C₄)-alkylamino,            or-   R¹ is a group of the formula —NR^(9A)R^(9B) or —OR¹⁰, wherein    -   R^(9A) and R^(9B) are independently selected from the group        consisting of hydrogen, (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl and 4-        to 7-membered heterocycloalkyl, wherein        -   (i) said (C₃-C₇)-cycloalkyl and 4- to 7-membered            heterocycloalkyl are optionally substituted with one or two            substituents independently selected from the group            consisting of fluoro, difluoromethyl, trifluoromethyl,            (C₁-C₄)-alkyl, oxo, hydroxy, difluoromethoxy,            trifluoromethoxy, (C₁-C₄)-alkoxy, amino,            mono-(C₁-C₄)-alkylamino and di-(C₁-C₄)-alkylamino,        -   and        -   (ii) said (C₁-C₆)-alkyl is optionally substituted with one,            two or three substituents independently selected from the            group consisting of fluoro, trifluoromethyl, hydroxy,            (C₁-C₄)-alkoxy, amino, mono-(C₁-C₄)-alkylamino,            di-(C₁-C₄)-alkylamino, (C₃-C₇)-cycloalkyl, phenyl, 4- to            7-membered heterocycloalkyl and 5- to 10-membered            heteroaryl,            -   wherein said (C₃-C₇)-cycloalkyl, phenyl, 4- to                7-membered heterocycloalkyl and 5- to 10-membered                heteroaryl substituents in turn are optionally                substituted with one or two residues independently                selected from the group consisting of fluoro, chloro,                bromo, difluoromethyl, trifluoromethyl, (C₁-C₄)-alkyl,                oxo, hydroxy, difluoromethoxy, trifluoromethoxy,                (C₁-C₄)-alkoxy, amino, mono-(C₁-C₄)-alkylamino and                di-(C₁-C₄)-alkylamino,    -   or    -   R^(9A) and R^(9B) are joined and, taken together with the        nitrogen atom to which they are attached, form a 4- to        7-membered heterocycloalkyl ring, which may contain a second        ring heteroatom selected from N, O and S, and which is        optionally substituted with one or two substituents        independently selected from the group consisting of fluoro,        (C₁-C₄)-alkyl, oxo, hydroxy, (C₁-C₄)-alkoxy, amino,        mono-(C₁-C₄)-alkylamino, di-(C₁-C₄)-alkylamino and        (C₃-C₆)-cycloalkyl,    -   R¹⁰ is selected from the group consisting of (C₁-C₆)-alkyl,        (C₃-C₇)-cycloalkyl and 4- to 7-membered heterocycloalkyl,        wherein        -   (i) said (C₃-C₇)-cycloalkyl and 4- to 7-membered            heterocycloalkyl are optionally substituted with one or two            substituents independently selected from the group            consisting of fluoro, difluoromethyl, trifluoromethyl,            (C₁-C₄)-alkyl, oxo, hydroxy, difluoromethoxy,            trifluoromethoxy, (C₁-C₄)-alkoxy, amino,            mono-(C₁-C₄)-alkylamino and di-(C₁-C₄)-alkylamino,        -   and        -   (ii) said (C₁-C₆)-alkyl is optionally substituted with one,            two or three substituents independently selected from the            group consisting of fluoro, trifluoromethyl, hydroxy,            (C₁-C₄)-alkoxy, amino, mono-(C₁-C₄)-alkylamino,            di-(C₁-C₄)-alkylamino, (C₃-C₇)-cycloalkyl, phenyl, 4- to            7-membered heterocycloalkyl and 5- to 10-membered            heteroaryl,            -   wherein said (C₃-C₇)-cycloalkyl, phenyl, 4- to                7-membered heterocycloalkyl and 5- to 10-membered                heteroaryl substituents in turn are optionally                substituted with one or two residues independently                selected from the group consisting of fluoro, chloro,                bromo, difluoromethyl, trifluoromethyl, (C₁-C₄)-alkyl,                oxo, hydroxy, difluoromethoxy, trifluoromethoxy,                (C₁-C₄)-alkoxy, amino, mono-(C₁-C₄)-alkylamino and                di-(C₁-C₄)-alkylamino,-   R² is hydrogen, fluoro, chloro or methyl,-   R³ is hydrogen, (C₁-C₄)-alkyl or cyclopropyl,-   R⁴ is cyano or aminocarbonyl,-   R⁵ is selected from the group consisting of (C₁-C₆)-alkyl,    (C₃-C₇)-cycloalkyl, phenyl and 5- or 6-membered heteroaryl, wherein    -   (i) said (C₃-C₇)-cycloalkyl, phenyl and 5- or 6-membered        heteroaryl are optionally substituted with one or two        substituents independently selected from the group consisting of        fluoro, chloro, bromo, cyano, difluoromethyl, trifluoromethyl,        (C₁-C₄)-alkyl, hydroxy, difluoromethoxy, trifluoromethoxy,        (C₁-C₄)-alkoxy, amino, mono-(C₁-C₄)-alkylamino and        di-(C₁-C₄)-alkylamino,    -   and    -   (ii) said (C₁-C₆)-alkyl is optionally substituted with up to        three fluoro atoms or with one or two substituents independently        selected from the group consisting of trifluoromethyl, hydroxy,        (C₁-C₄)-alkoxy, amino, mono-(C₁-C₄)-alkylamino,        di-(C₁-C₄)-alkylamino, (C₃-C₇)-cycloalkyl, phenyl, 4- to        7-membered heterocycloalkyl and 5- or 6-membered heteroaryl,        -   wherein the alkyl groups of said (C₁-C₄)-alkoxy,            mono-(C₁-C₄)-alkylamino and di-(C₁-C₄)-alkylamino            substituents in turn are optionally substituted with up to            three fluoro atoms or with one or two residues independently            selected from the group consisting of trifluoromethyl,            hydroxy, (C₁-C₄)-alkoxy, amino, mono-(C₁-C₄)-alkylamino,            di-(C₁-C₄)-alkylamino and 4- to 7-membered heterocycloalkyl,        -   and wherein        -   said (C₃-C₇)-cycloalkyl, phenyl, 4- to 7-membered            heterocycloalkyl and 5- or 6-membered heteroaryl groups in            turn are optionally substituted with one or two residues            independently selected from the group consisting of fluoro,            chloro, cyano, trifluoromethyl, (C₁-C₄)-alkyl, oxo, hydroxy,            (C₁-C₄)-alkoxy, amino, mono-(C₁-C₄)-alkylamino and            di-(C₁-C₄)-alkylamino,            or-   R⁵ is (C₁-C₄)-alkoxycarbonyl, aminocarbonyl,    mono-(C₁-C₄)-alkylaminocarbonyl or di-(C₁-C₄)-allcylaminocarbonyl,    or-   R³ and R⁵ are joined and, taken together with the nitrogen and the    carbon atom to which they are attached, form a fused ring of the    formula

-   -   wherein    -   G is —CH₂—, —C(CH₃)₂—, —CH(CF₃)—, —O— or —NR¹¹—, wherein        -   R¹¹ is hydrogen or (C₁-C₄)-alkyl,    -   and    -   R^(12A) and R^(12B) are independently hydrogen or fluoro,        or

-   R⁴ and R⁵ are joined and, taken together with the carbon atoms to    which they are attached, form a fused lactone or lactame ring of the    formula

-   -   wherein    -   M is —O— or —NR¹³—, wherein        -   R¹³ is hydrogen or (C₁-C₄)-alkyl.

The compounds according to this invention can also be present in theform of their salts, hydrates and/or solvates.

Salts for the purposes of the present invention are preferablypharmaceutically acceptable salts of the compounds according to theinvention (for example, see S. M. Berge et al., “Pharmaceutical Salts”,J. Pharm. Sci. 1977, 66, 1-19).

Pharmaceutically acceptable salts include acid addition salts of mineralacids, carboxylic acids and sulfonic acids, for example salts ofhydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid,methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid,benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionicacid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid,maleic acid and benzoic acid.

Pharmaceutically acceptable salts also include salts of customary bases,such as for example and preferably alkali metal salts (for examplesodium and potassium salts), alkaline earth metal salts (for examplecalcium and magnesium salts), and ammonium salts derived from ammonia ororganic amines, such as illustratively and preferably ethylamine,diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine,diethanolamine, triethanolamine, dicyclohexylamine,dimethylaminoethanol, dibenzylamine, N-methylmorpholine,N-methylpiperidine, dihydroabietylamine, arginine, lysine, andethylenediamine.

Hydrates of the compounds of the invention or their salts arestoichiometric compositions of the compounds with water, such as, forexample, hemi-, mono-, or dihydrates.

Solvates of the compounds of the invention or their salts arestoichiometric compositions of the compounds with solvents.

The compounds of this invention may, either by nature of asymmetriccenters or by restricted rotation, be present in the form of isomers(enantiomers, diastereomers). Any isomer may be present in which theasymmetric center is in the (R)-, (S)-, or (R,S) configuration.

It will also be appreciated that when two or more asymmetric centers arepresent in the compounds of the invention, several diastereomers andenantiomers of the exemplified structures will often be possible, andthat pure diastereomers and pure enantiomers represent preferredembodiments. It is intended that pure stereoisomers, pure diastereomers,pure enantiomers, and mixtures thereof, are within the scope of theinvention.

Geometric isomers by nature of substituents about a double bond or aring may be present in cis (=Z—) or trans (=E—) form, and both isomericforms are encompassed within the scope of this invention.

All isomers, whether separated, pure, partially pure, or in racemicmixture, of the compounds of this invention are encompassed within thescope of this invention. The purification of said isomers and theseparation of said isomeric mixtures may be accomplished by standardtechniques known in the art. For example, diastereomeric mixtures can beseparated into the individual isomers by chromatographic processes orcrystallization, and racemates can be separated into the respectiveenantiomers either by chromatographic processes on chiral phases or byresolution.

In addition, all possible tautomeric forms of the compounds describedabove are included according to the present invention.

Unless otherwise stated, the following definitions apply for thesubstituents and residues used throughout this specification and claims:

Alkyl in general represents a straight-chain or branched saturatedhydrocarbon radical having 1 to 6, preferably 1 to 4, more preferably 1to 3 carbon atoms. Non-limiting examples include methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl, tert.-butyl, pentyl,isopentyl, neopentyl, hexyl, isohexyl. The same applies to radicals suchas alkoxy, monoalkylamino, dialkylamino, and the like.

Alkoxy illustratively and preferably represents methoxy, ethoxy,n-propoxy, isopropoxy, n-butoxy and tert.-butoxy. The same applies toradicals such as alkoxycarbonyl.

Alkoxycarbonyl illustratively and preferably represents methoxycarbonyl,ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyland tert.-butoxycarbonyl.

Monoalkylamino in general represents an amino radical having one alkylresidue attached to the nitrogen atom. Non-limiting examples includemethylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino,tert.-butylamino. The same applies to radicals such asmonoalkylaminocarbonyl.

Dialkylamino in general represents an amino radical having twoindependently selected alkyl residues attached to the nitrogen atom.Non-limiting examples include N,N-dimethylamino, N,N-diethylamino,N,N-diisopropylamino, N-ethyl-N-methylamino, N-methyl-N-n-propylamino,N-isopropyl-N-n-propylamino, N-tert.-butyl-N-methylamino. The sameapplies to radicals such as dialkylaminocarbonyl.

Monoalkylaminocarbonyl illustratively and preferably representsmethylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl,isopropylaminocarbonyl, n-butylaminocarbonyl andtert.-butylaminocarbonyl.

Dialkylaminocarbonyl illustratively and preferably representsN,N-dimethylaminocarbonyl, N,N-diethylaminocarbonyl,N,N-diisopropylaminocarbonyl, N-ethyl-N-methylaminocarbonyl,N-methyl-N-n-propylaminocarbonyl, N-isopropyl-N-n-propylaminocarbonyland N-tert.-butyl-N-methylaminocarbonyl.

Cycloalkyl in general represents a mono- or bicyclic saturatedhydrocarbon radical having 3 to 7, preferably 3 to 6 carbon atoms.Preference is given to monocyclic cycloalkyl radicals. Non-limitingexamples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, bicyclo-[2.2.1]heptyl.

Heterocycloalkyl in general represents a mono- or bicyclic, saturatedheterocyclic radical having a total number of 4 to 7, preferably 4 to 6ring atoms, including 3 to 6, preferably 3 to 5 carbon atoms and up to 2heteroatoms and/or hetero-groups independently selected from the groupconsisting of N, O, S, SO and SO₂, which ring system can be bonded via aring carbon atom or, if possible, via a ring nitrogen atom. Non-limitingexamples include azetidinyl, oxetanyl, thietanyl, pyrrolidinyl,pyrazolidinyl, tetrahydrofuranyl, thiolanyl, sulfolanyl, 1,3-dioxolanyl,1,3-oxazolidinyl, 1,3-thiazolidinyl, piperidinyl, piperazinyl,tetrahydropyranyl, tetrahydrothiopyranyl, 1,3-dioxanyl, 1,4-dioxanyl,morpholinyl, thiomorpholinyl, 1,1-dioxidothiomorpholinyl,perhydroazepinyl, perhydro-1,4-diazepinyl, perhydro-1,4-oxazepinyl,7-azabicyclo[2.2.1]heptyl, 3-azabicyclo-[3.2.0]heptyl,7-azabicyclo[4.1.0]heptyl, 2,5-diazabicyclo[2.2.1]heptyl,2-oxa-5-azabicyclo[2.2.1]-heptyl. Preference is given to 4- to6-membered monocyclic heterocycloalkyl radicals having up to 2heteroatoms selected from the group consisting of N and O, such asillustratively and preferably azetidinyl, oxetanyl, tetrahydrofuranyl,1,3-dioxolanyl, pyrrolidinyl, tetrahydropyranyl, 1,4-dioxanyl,piperidinyl, piperazinyl and morpholinyl.

Azetidino, pyrrolidino, piperidino, piperazino or morpholinospecifically refers to the respective heterocycloalkyl radical bonded tothe rest of the molecule via a ring nitrogen atom.

Heteroaryl in general represents a mono- or bicyclic, aromaticheterocyclic radical having a total number of 5 to 10 ring atoms,including 2 to 9 carbon atoms and up to 3 heteroatoms independentlyselected from the group consisting of N, O and S, which ring system canbe bonded via a ring carbon atom or, if possible, via a ring nitrogenatom. Non-limiting examples include furyl, pyrrolyl, thienyl, pyrazolyl,imidazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, triazolyl,oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl,triazinyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl,benzothiazolyl, benzotriazolyl, benzothiadiazolyl, indolyl, isoindolyl,indazolyl, quinolinyl, isoquinolinyl, naphthyridinyl, quinazolinyl,quinoxalinyl, phthalazinyl, imidazopyridinyl, pyrazolopyridinyl,pyrrolopyrimidinyl. Preference is given to 6-membered heteroarylradicals having up to 2 nitrogen atoms, such as pyridyl, pyrimidyl,pyridazinyl and pyrazinyl, and to 5-membered heteroaryl radicals havingup to 2 heteroatoms selected from the group consisting of N, O and S,such as illustratively and preferably thienyl, furyl, pyrrolyl,pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isothiazolyl and isoxazolyl.

Halogen represents radicals of fluorine, chlorine, bromine and iodine.Preference is given to radicals of fluorine and chlorine.

Oxo represents a doubly bonded oxygen atom.

Throughout this document, for the sake of simplicity, the use ofsingular language is given preference over plural language, but isgenerally meant to include the plural language if not otherwise stated.E.g., the expression “A method of treating a disease in a patient,comprising administering to a patient an effective amount of a compoundof formula (I)” is meant to include the simultaneous treatment of morethan one disease as well as the administration of more than one compoundof formula (I).

In a preferred embodiment, the present invention relates to compounds ofgeneral formula (I), wherein A is —S(═O)₂— and D is —CH₂—.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), wherein

-   A is —C(═O)—    and-   D is —CH₂—, —O— or —NR⁷—, wherein    -   R⁷ is hydrogen or (C₁-C₄)-alkyl.

In a further preferred embodiment, the present invention relates tocompounds of general formula (I), wherein

-   E is —CR^(8A)R^(8B)—, wherein    -   R^(8A) and R^(8B) are independently hydrogen or (C₁-C₄)-alkyl,    -   or    -   R^(8A) and R^(8B) are joined and, taken together with the carbon        atom to which they are attached, form a cyclopropyl ring.

In yet another preferred embodiment, the present invention relates tocompounds of general formula (I), wherein R⁴ is cyano.

In a more preferred embodiment, the present invention relates tocompounds of general formula (I), wherein

-   A is —C(═O)—,-   D is —CH₂—, —O—, —NH— or —N(CH₃)—,-   E is —CR^(8A)R^(8B)— or *—CR^(8A)R^(8B)—CH₂—**, wherein    -   * denotes the link to the dihydropyridine ring,    -   ** denotes the link to the D group,    -   and    -   R^(8A) and R^(8B) are independently hydrogen or methyl,    -   or    -   R^(8A) and R^(8B) are joined and, taken together with the carbon        atom to which they are attached, form a cyclopropyl ring,-   R¹ is selected from the group consisting of hydrogen, (C₁-C₆)-alkyl,    (C₃-C₆)-cycloalkyl, phenyl, 4- to 6-membered heterocycloalkyl and 5-    or 6-membered heteroaryl, wherein    -   (i) said (C₃-C₆)-cycloalkyl, phenyl, 4- to 6-membered        heterocycloalkyl and 5- or 6-membered heteroaryl are optionally        substituted with one or two substituents independently selected        from the group consisting of fluoro, chloro, difluoromethyl,        trifluoromethyl, (C₁-C₄)-alkyl, oxo, hydroxy, difluoromethoxy,        trifluoromethoxy, (C₁-C₄)-alkoxy, amino,        mono-(C₁-C₄)-alkylamino, di-(C₁-C₄)-alkylamino and 4- to        6-membered heterocycloalkyl,        -   wherein the alkyl groups of said (C₁-C₄)-alkoxy,            mono-(C₁-C₄)-alkylamino and di-(C₁-C₄)-alkylamino            substituents in turn are optionally substituted with            hydroxy, methoxy or ethoxy,    -   and    -   (ii) said (C₁-C₆)-alkyl is optionally substituted with one, two        or three substituents independently selected from the group        consisting of fluoro, trifluoromethyl, hydroxy, (C₁-C₄)-alkoxy,        amino, mono-(C₁-C₄)-alkylamino, di-(C₁-C₄)-alkylamino,        (C₃-C₆)-cycloalkyl, 4- to 6-membered heterocycloalkyl and 5- or        6-membered heteroaryl,        -   wherein said (C₃-C₆)-cycloalkyl, 4- to 6-membered            heterocycloalkyl and 5- or 6-membered heteroaryl            substituents in turn are optionally substituted with one or            two residues independently selected from the group            consisting of fluoro, chloro, difluoromethyl,            trifluoromethyl, (C₁-C₄)-alkyl, oxo, hydroxy,            (C₁-C₄)-alkoxy, amino, mono-(C₁-C₄)-alkylamino and            di-(C₁-C₄)-alkylamino,            or-   R¹ is a group of the formula —NR^(9A)R^(9B) or —OR¹⁰, wherein    -   R^(9A) is hydrogen or (C₁-C₄)-alkyl optionally substituted with        one or two substituents independently selected from the group        consisting of hydroxy, (C₁-C₄)-alkoxy, amino,        mono-(C₁-C₄)-alkylamino and di-(C₁-C₄)-alkylamino,    -   R^(9B) is selected from the group consisting of hydrogen,        (C₁-C₆)-alkyl, (C₃-C₆)-cycloalkyl and 4- to 6-membered        heterocycloalkyl, wherein        -   (i) said (C₃-C₆)-cycloalkyl and 4- to 6-membered            heterocycloalkyl are optionally substituted with one or two            substituents independently selected from the group            consisting of fluoro, difluoromethyl, trifluoromethyl,            (C₁-C₄)-alkyl, oxo, hydroxy, (C₁-C₄)-alkoxy, amino,            mono-(C₁-C₄)-alkylamino and di-(C₁-C₄)-alkylamino,        -   and        -   (ii) said (C₁-C₆)-alkyl is optionally substituted with one,            two or three substituents independently selected from the            group consisting of fluoro, trifluoromethyl, hydroxy,            (C₁-C₄)-alkoxy, amino, mono-(C₁-C₄)-alkylamino,            di-(C₁-C₄)-alkylamino, (C₃-C₆)-cycloalkyl, 4- to 6-membered            heterocycloalkyl and 5- or 6-membered heteroaryl,            -   wherein said (C₃-C₆)-cycloalkyl, 4- to 6-membered                heterocycloalkyl and 5- or 6-membered heteroaryl                substituents in turn are optionally substituted with one                or two residues independently selected from the group                consisting of fluoro, chloro, difluoromethyl,                trifluoromethyl, (C₁-C₄)-alkyl, oxo, hydroxy,                (C₁-C₄)-alkoxy, amino, mono-(C₁-C₄)-alkylamino and                di-(C₁-C₄)-alkylamino,    -   or    -   R^(9A) and R^(9B) are joined and, taken together with the        nitrogen atom to which they are attached, form a 4- to        6-membered heterocycloalkyl ring, which may contain a second        ring heteroatom selected from N and O, and which is optionally        substituted with one or two substituents independently selected        from the group consisting of fluoro, (C₁-C₄)-alkyl, oxo,        hydroxy, (C₁-C₄)-alkoxy, amino, mono-(C₁-C₄)-alkylamino and        di-(C₁-C₄)-alkylamino,    -   R¹⁰ is selected from the group consisting of (C₁-C₆)-alkyl,        (C₃-C₆)-cycloalkyl and 4- to 6-membered heterocycloalkyl,        wherein        -   (i) said (C₃-C₆)-cycloalkyl and 4- to 6-membered            heterocycloalkyl are optionally substituted with one or two            substituents independently selected from the group            consisting of fluoro, difluoromethyl, trifluoromethyl,            (C₁-C₄)-alkyl, oxo, hydroxy, (C₁-C₄)-alkoxy, amino,            mono-(C₁-C₄)-alkylamino and di-(C₁-C₄)-alkylamino,        -   and        -   (ii) said (C₁-C₆)-alkyl is optionally substituted with one,            two or three substituents independently selected from the            group consisting of fluoro, trifluoromethyl, hydroxy,            (C₁-C₄)-alkoxy, amino, mono-(C₁-C₄)-alkylamino,            di-(C₁-C₄)-alkylamino, (C₃-C₆)-cycloalkyl, 4- to 6-membered            heterocycloalkyl and 5- or 6-membered heteroaryl,            -   wherein said (C₃-C₆)-cycloalkyl, 4- to 6-membered                heterocycloalkyl and 5- or 6-membered heteroaryl                substituents in turn are optionally substituted with one                or two residues independently selected from the group                consisting of fluoro, chloro, difluoromethyl,                trifluoromethyl, (C₁-C₄)-alkyl, oxo, hydroxy,                (C₁-C₄)-alkoxy, amino, mono-(C₁-C₄)-alkylamino and                di-(C₁-C₄)-alkylamino,-   R² is hydrogen or fluoro,-   R³ is hydrogen or (C₁-C₄)-alkyl,-   R⁴ is cyano,-   R⁵ is selected from the group consisting of (C₁-C₄)-alkyl,    cyclopropyl, phenyl and 5- or 6-membered heteroaryl, wherein    -   (i) said cyclopropyl is optionally substituted with one or two        substituents independently selected from the group consisting of        fluoro, trifluoromethyl and methyl,    -   (ii) said phenyl and 5- or 6-membered heteroaryl are optionally        substituted with one or two substituents independently selected        from the group consisting of fluoro, chloro, cyano,        difluoromethyl, trifluoromethyl, (C₁-C₄)-alkyl and        (C₁-C₄)-alkoxy,    -   and    -   (iii) said (C₁-C₄)-alkyl is optionally substituted with up to        three fluoro atoms or with one or two substituents independently        selected from the group consisting of (C₁-C₄)-alkoxy, amino,        mono-(C₁-C₄)-alkylamino, di-(C₁-C₄)-alkylamino,        (C₃-C₆)-cycloalkyl, phenyl, 4- to 6-membered heterocycloalkyl        and 5-membered heteroaryl,        -   wherein the alkyl groups of said (C₁-C₄)-alkoxy,            mono-(C₁-C₄)-alkylamino and di-(C₁-C₄)-alkylamino            substituents in turn are optionally substituted with up to            three fluoro atoms or with one or two residues independently            selected from the group consisting of (C₁-C₄)-alkoxy, amino,            mono-(C₁-C₄)-alkylamino, di-(C₁-C₄)-alkylamino and 4- to            6-membered heterocycloalkyl,        -   and wherein        -   said (C₃-C₆)-cycloalkyl, phenyl, 4- to 6-membered            heterocycloalkyl and 5-membered heteroaryl groups in turn            are optionally substituted with one or two residues            independently selected from the group consisting of fluoro,            chloro, cyano, trifluoromethyl, (C₁-C₄)-alkyl, oxo,            (C₁-C₄)-alkoxy, amino, mono-(C₁-C₄)-alkylamino and            di-(C₁-C₄)-alkylamino,            or-   R³ and R⁵ are joined and, taken together with the nitrogen and the    carbon atom to which they are attached, form a fused ring of the    formula

-   -   wherein    -   R^(12A) and R^(12B) are independently hydrogen or fluoro,        or

-   R⁴ and R⁵ are joined and, taken together with the carbon atoms to    which they are attached, form a fused lactone ring of the formula

In a particularly preferred embodiment, the present invention relates tocompounds of general formula (I), wherein

-   A is —C(═O)—,-   D is —O—,-   E is —CH₂—, —CH(CH₃)— or —C(CH₃)₂—,-   R¹ is selected from the group consisting of hydrogen, (C₁-C₄)-alkyl,    phenyl and 5- or 6-membered heteroaryl, wherein    -   (i) said phenyl and 5- or 6-membered heteroaryl are optionally        substituted with one or two substituents independently selected        from the group consisting of fluoro, chloro, difluoromethyl,        trifluoromethyl, (C₁-C₃)-alkyl, (C₁-C₃)-alkoxy, amino,        mono-(C₁-C₃)-alkylamino, di-(C₁-C₃)-alkylamino and 4- to        6-membered heterocycloalkyl,        -   wherein the alkyl groups of said (C₁-C₃)-alkoxy,            mono-(C₁-C₃)-alkylamino and di-(C₁-C₃)-alkylamino            substituents in turn are optionally substituted with methoxy            or ethoxy,    -   and    -   (ii) said (C₁-C₄)-alkyl is optionally substituted with up to        three fluoro atoms or with one or two substituents independently        selected from the group consisting of (C₁-C₃)-alkoxy, amino,        mono-(C₁-C₃)-alkylamino, di-(C₁-C₃)-alkylamino and 4- to        6-membered heterocycloalkyl,        -   wherein said 4- to 6-membered heterocycloalkyl substituent            in turn is optionally substituted with one or two residues            independently selected from the group consisting of fluoro,            trifluoromethyl, methyl, ethyl, oxo, methoxy, ethoxy, amino,            methylamino, ethylamino, dimethylamino and diethylamino,            or-   R¹ is a group of the formula —NR^(9A)R^(9B) or —OR¹⁰, wherein    -   R^(9A) is hydrogen or (C₁-C₄)-alkyl optionally substituted with        hydroxy, methoxy, ethoxy, amino, methylamino, ethylamino,        dimethylamino or diethylamino,    -   R^(9B) is hydrogen or (C₁-C₄)-alkyl optionally substituted with        up to three fluoro atoms or with one or two substituents        independently selected from the group consisting of hydroxy,        (C₁-C₃)-alkoxy, amino, mono-(C₁-C₃)-alkylamino,        di-(C₁-C₃)-alkylamino and 4- to 6-membered heterocycloalkyl,        -   wherein said 4- to 6-membered heterocycloalkyl substituent            in turn is optionally substituted with one or two residues            independently selected from the group consisting of fluoro,            trifluoromethyl, methyl, ethyl, oxo, methoxy, ethoxy, amino,            methylamino, ethylamino, dimethylamino and diethylamino,    -   or    -   R^(9A) and R^(9B) are joined and, taken together with the        nitrogen atom to which they are attached, form a 4- to        6-membered heterocycloalkyl ring, which may contain a second        ring heteroatom selected from N and O, and which is optionally        substituted with one or two substituents independently selected        from the group consisting of fluoro, methyl, ethyl, oxo,        methoxy, ethoxy, amino, methylamino, ethylamino, dimethylamino        and diethylamino,    -   R¹⁰ is (C₁-C₄)-alkyl optionally substituted with up to three        fluoro atoms or with one or two substituents independently        selected from the group consisting of hydroxy, (C₁-C₃)-alkoxy,        amino, mono-(C₁-C₃)-alkylamino, di-(C₁-C₃)-alkylamino and 4- to        6-membered heterocycloalkyl,        -   wherein said 4- to 6-membered heterocycloalkyl substituent            in turn is optionally substituted with one or two residues            independently selected from the group consisting of fluoro,            trifluoromethyl, methyl, ethyl, oxo, methoxy, ethoxy, amino,            methylamino, ethylamino, dimethylamino and diethylamino,-   R² is hydrogen or fluoro,-   R³ is hydrogen or methyl,-   R⁴ is cyano,    and-   R⁵ is selected from the group consisting of (C₁-C₄)-alkyl, phenyl,    pyridyl, pyrimidinyl, oxazolyl and isoxazolyl, wherein    -   (i) said phenyl, pyridyl, pyrimidinyl, oxazolyl and isoxazolyl        are optionally substituted with one or two substituents        independently selected from the group consisting of fluoro,        chloro, difluoromethyl, trifluoromethyl, methyl, ethyl, methoxy        and ethoxy,    -   and    -   (ii) said (C₁-C₄)-alkyl is optionally substituted with up to        three fluoro atoms or with a substituent selected from the group        consisting of (C₁-C₃)-alkoxy, amino, mono-(C₁-C₃)-alkylamino,        di-(C₁-C₃)-alkylamino, phenyl, 4- to 6-membered heterocycloalkyl        and 5-membered heteroaryl,        -   wherein said phenyl and 5-membered heteroaryl substituents            in turn are optionally substituted with one or two residues            independently selected from the group consisting of fluoro,            chloro, trifluoromethyl, methyl, ethyl and amino,        -   and wherein        -   the alkyl groups of said (C₁-C₃)-alkoxy,            mono-(C₁-C₃)-alkylamino and di-(C₁-C₃)-alkylamino            substituents in turn are optionally substituted with up to            three fluoro atoms or with a residue selected from the group            consisting of methoxy, ethoxy, amino, methylamino,            ethylamino, dimethylamino, diethylamino, azetidino,            pyrrolidino, piperidino, piperazino and morpholino,        -   and wherein        -   said 4- to 6-membered heterocycloalkyl substituent as well            as said azetidino, pyrrolidino, piperidino, piperazino and            morpholino groups in turn are optionally substituted with            one or two residues independently selected from the group            consisting of fluoro, methyl, ethyl and oxo.

In an especially preferred embodiment, the present invention relates tocompounds of general formula (I), wherein

-   A is —C(═O)—,-   D is —O—,-   E is —CH₂—,-   R¹ is hydrogen, methyl or ethyl,-   R² is hydrogen or fluoro,-   R³ is hydrogen or methyl,-   R⁴ is cyano,    and-   R⁵ is (C₁-C₄)-alkyl optionally substituted with methoxy, ethoxy or    up to three fluoro atoms,    -   or    -   is phenyl optionally substituted with one or two substituents        independently selected from the group consisting of fluoro,        chloro, methyl and trifluoromethyl.

The definitions of residues indicated specifically in the respectivecombinations or preferred combinations of residues are also replaced asdesired by definitions of residues of other combinations, irrespectiveof the particular combinations indicated for the residues. Combinationsof two or more of the abovementioned preferred ranges are particularlypreferred.

In another embodiment, the present invention relates to a process forpreparing the compounds of general formula (I), wherein R³ is hydrogen,characterized in that an indazolyl aldehyde of formula (II)

wherein R¹ and R² have the meanings described above,is reacted either

-   [A] with a compound of formula (III)

-   -   or a sodium enolate thereof, wherein R⁴ and R⁵ have the meanings        described above,    -   in the presence of an acid, an acid/base combination and/or a        dehydrating agent to give a compound of formula (IV)

-   -   wherein R¹, R², R⁴ and R⁵ have the meanings described above,    -   and the latter is then condensed with a compound of formula (V)

-   -   wherein A, D and E have the meanings described above,    -   in the presence of an ammonia source such as ammonium acetate to        give the compound of formula (I-A)

-   -   wherein A, D, E, R¹, R², R⁴ and R⁵ have the meanings described        above,        or

-   [B] with a compound of formula (V)

-   -   wherein A, D and E have the meanings described above,    -   optionally in the presence of a base and/or a dehydrating agent        to yield a compound of formula (VI)

-   -   wherein A, D, E, R¹ and R² have the meanings described above,    -   and the latter is then condensed with a compound of formula        (VII)

-   -   wherein R⁴ and R⁵ have the meanings described above,    -   in the presence of an acid to give the compound of formula (I-A)

-   -   wherein A, D, E, R¹, R², R⁴ and R⁵ have the meanings described        above,        optionally followed, where appropriate, by (i) separating the        compounds (I-A) into their respective enantiomers and/or        diastereomers, preferably using chromatographic methods,        and/or (ii) converting the compounds (I-A) into their respective        hydrates, solvates, salts and/or hydrates or solvates of the        salts by treatment with the corresponding solvents and/or acids        or bases.

Process steps (II)+(III)→(IV), (IV)+(V)→(I-A), (II)+(V)→(VI) and(VI)+(VII)→(I-A) are generally carried out in an inert solvent at atemperature range from +20° C. to the boiling point of the solvent underatmospheric pressure.

Inert solvents suitable for this purpose are, for example, alcohols suchas methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanolor n-pentanol, hydrocarbons such as hexane, cyclohexane, benzene,toluene or xylene, halohydrocarbons such as dichloromethane,trichloromethane, tetrachloromethane, trichloroethane,1,2-dichloroethane, chlorobenzene or chlorotoluene, ethers such astetrahydrofuran, 1,4-dioxane or 1,2-dimethoxyethane, or other solventssuch as acetonitrile or acetic acid. It is likewise possible to usemixtures of these solvents. Reactions (II)+(III)-4 (IV) and(II)+(V)→(VI) are preferably performed in dichloromethane, toluene,ethanol, n-propanol, isopropanol, n-butanol or n-pentanol at therespective reflux temperature under atmospheric pressure, and reactions(IV)+(V)→(I-A) and (VI)+(VII)→(I-A) are preferably carried out in aceticacid also at reflux temperature under atmospheric pressure.

Reaction (II)+(III)→(IV) can advantageously take place in the presenceof an acid, an acid/base combination and/or a dehydrating agent such as,for example, molecular sieves. Examples of suitable acid catalysts areacetic acid, trifluoroacetic acid, methanesulfonic acid orp-toluene-sulfonic acid; suitable bases are in particular piperidine orpyridine. Depending on the reactivity of the components, conversion(II)+(V)→(VI) may be performed without further auxiliary reagents, or itcan be facilitated by a customary amine base, such as piperidine, and/ora dehydrating agent, such as molecular sieves. Reactions (IV)+(V)→(I-A)and (VI)+(VII)→(I-A) are usually carried out in the presence of an acid;preferably, acetic acid is used both as acid catalyst and solvent.

Suitable ammonia sources for reaction (IV)+(V)→(I-A) are, for example,ammonium formate, ammonium acetate, ammonium chloride or ammoniumhydrogensulfate; preference is given to ammonium acetate [for thesynthesis of 1,4-dihydropyridines in general, see, for example, D. M.Stout, A. I. Meyers, Chem. Rev. 1982, 82, 223-243; H. Meier et al.,Liebigs Ann. Chem. 1977, 1888; H. Meier et al., ibid. 1977, 1895; H.Meier et al., ibid. 1976, 1762; F. Bossert et al., Angew. Chem. 1981,93, 755].

Compounds of the invention having the formula (I-B)

wherein E, R¹, R², R⁴ and R⁵ have the meanings described above,and

-   D¹ represents —O— or —NR⁷—, wherein R⁷ has the meaning described    above,    may also be prepared by a three-component condensation reaction of    the indazolyl aldehyde (II)

wherein R¹ and R² have the meanings described above,with an enamine of formula (VII)

wherein R⁴ and R⁵ have the meanings described above,and a compound of formula (VIII)

wherein E and D¹ have the meanings described above,

-   T¹ represents (C₁-C₄)-alkyl,    and-   PG^(A) represents a suitable hydroxy- or amino-protecting group,    such as acetyl, trimethylsilyl, tetrahydropyranyl,    tert-butoxycarbonyl or benzyloxycarbonyl, respectively,    to give an intermediate compound of formula (IX)

wherein D¹, E, PG^(A), T¹, R¹, R², R⁴ and R⁵ have the meanings describedabove,which is then deprotected and cyclized to yield the target compound offormula (I-B).

The condensation reaction (II)+(VII)+(VIII)→(IX) is preferably carriedout in an alcoholic solvent such as methanol, ethanol, n-propanol,isopropanol, n-butanol, tert-butanol or n-pentanol, optionally incombination with an acid catalyst such as acetic acid. The conversion isgenerally performed at a temperature range from +20° C. to +150° C.,preferably from +80° C. to +120° C., under atmospheric pressure.

The removal of the protecting group PG^(A) in process step (IX)→(I-B) isgenerally carried out by standard methods well known in the art [see,for example, T. W. Greene and P. G. M. Wuts, Protective Groups inOrganic Synthesis, Wiley, New York, 1999]. As a hydroxy-protectinggroup, acetyl is preferably used. In this case, deprotection andsubsequent lactone formation [D¹=O in (I-B)] may be accomplished in aone-pot procedure, i.e. without isolation of the deprotectedintermediate, by treating the compound (IX) with an aqueous solution ofa strong acid, such as hydrogen chloride, hydrogen bromide ortrifluoroacetic acid, at elevated temperature (e.g. from +50° C. to+120° C.).

For nitrogen protection, tert-butoxycarbonyl (Boc) is preferablyemployed as group PG^(A). Deprotection by standard treatment withanhydrous hydrogen chloride or trifluoroacetic acid, and finalcyclization to lactame (I-B) [D¹=NR⁷] by exposing the intermediate aminesalt to a customary base may again be performed using a one-potprocedure or in two separate steps.

Compounds of formula (I), wherein R³ is (C₁-C₄)-alkyl or cyclopropyl,can be prepared by converting the compound of formula (I-A) by standardmethods first into the indazole N¹-protected derivative of formula (X)

wherein A, D, E, R¹, R², R⁴ and R⁵ have the meanings described above,and

-   PG^(B) represents a suitable indazole-protecting group, such as    tert-butoxycarbonyl, 2-(trimethylsilyl)ethoxymethyl or    p-methoxybenzyl,    followed by dihydropyridine N-alkylation with a compound of formula    (XI)

R^(3A)—Z  (XI),

wherein

-   R^(3A) represents (C₁-C₄)-alkyl or cyclopropyl,    and-   Z represents a leaving group such as halogen, mesylate, triflate or    tosylate,    in the presence of a base to afford a compound of formula (XII)

wherein A, D, E, PGB, R¹, R², R³A, R⁴ and R⁵ have the meanings describedabove,and subsequent removal of the protecting group PG^(B) using standardprocedures to give the compound of formula (I-C)

wherein A, D, E, R¹, R², R^(3A), R⁴ and R⁵ have the meanings describedabove.

Introduction and removal of the indazole-protecting group PG^(B) inprocess steps (I-A)→(X) and (XII)→(I-C), respectively, is generallycarried out by standard methods well known in the art [see, for example,T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis,Wiley, New York, 1999; M. Bodanszky and A. Bodanszky, The Practice ofPeptide Synthesis, Springer-Verlag, Berlin, 1984]. Preferably used asprotecting group in the above process is tert-butoxycarbonyl (Boc),2-(trimethylsilyl)ethoxymethyl (SEM) or p-methoxybenzyl (PMB). Theremoval of these groups is preferably carried out by reacting with astrong acid such as hydrogen chloride, hydrogen bromide ortrifluoroacetic acid in an inert solvent such as water, dioxane,dichloromethane or acetic acid; it is also possible, where appropriate,for the removal to be carried out without an additional inert solvent.When using the SEM group for indazole protection, cleavage mayalternatively be accomplished by treatment with a fluoride source suchas potassium fluoride or tetrabutylammonium fluoride in an inert solventsuch as tetrahydrofuran.

In some cases, however, it may be more convenient to perform thedihydropyridine N-alkylation step without prior blockade of the indazoleN¹-nitrogen, and to separate product mixtures that may result preferablyusing chromatographic methods.

Inert solvents for the alkylation reaction (X)+(XI)→(XII) are, forexample, ethers such as diethyl ether, methyl tert-butyl ether,tetrahydrofuran, 1,4-dioxane or 1,2-dimethoxyethane, hydrocarbons suchas benzene, toluene, xylene, hexane or cyclohexane, halohydrocarbonssuch as dichloromethane, trichloromethane, tetrachloromethane,1,2-dichloroethane, trichloroethane, tetrachloroethane, chlorobenzene orchlorotoluene, or other solvents such as acetonitrile,N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO),N,N′-dimethylpropylene urea (DMPU), N-methylpyrrolidinone (NMP) orpyridine. It is also possible to use mixtures of these solvents.Dichloromethane, tetrahydrofuran, dimethylformamide or mixtures thereofare preferably employed.

Bases suitable for process step (X)+(XI)→(XII) are in particular alkalimetal or alkaline earth metal carbonates such as lithium, sodium,potassium, calcium or caesium carbonate, alkali metal hydrides such assodium or potassium hydride, sterically hindered alkali alkoxides suchas sodium or potassium tert-butoxide, sterically hindered alkali amidessuch as lithium, sodium or potassium bis(trimethylsilyl)amide or lithiumdiisopropylamide, or organic amines such as triethylamine,N-methylmorpholine, N-methylpiperidine, N,N-diisopropylethylamine orpyridine. Potassium carbonate, caesium carbonate, sodium hydride ortriethylamine are preferably used.

The reaction (X)+(XI)→(XII) is generally performed under atmosphericpressure at a temperature range from −20° C. to +120° C., preferably at0° C. to +80° C.

Compounds of the invention having the formula (I-D)

wherein A, D, E, G, R¹, R², R^(12A) and R^(12B) have the meaningsdescribed above,can be prepared in close analogy to the condensation reactions describedabove by substituting the compound of formula (XIII)

wherein G, R^(12A) and R^(12B) have the meanings described above,for the compound of formula (VII) [cf. transformations (VI)+(VII)→(I-A)and (II)+(VII)+(VIII)→(IX), respectively]. Reaction parameters listedabove, such as solvents and acid catalysts, are applied correspondingly.

The compound of formula (XIII) may be prepared starting from a lactam offormula (XIV)

wherein G, R^(12A) and R^(12B) have the meanings described above, whichis first condensed via its lactim ether derivative of formula (XV)

wherein G, R^(12A) and R^(12B) have the meanings described above,with a cyanoacetate of formula (XVI)

wherein

-   T² represents (C₁-C₄)-alkyl or benzyl,    to give a compound of formula (XVII)

wherein G, T², R^(12A) and R^(12B) have the meanings described above,which upon ester cleavage and decarboxylation yields the cyano-enamineof formula (XIII) [see reaction scheme 4 below]. This intermediate isusually employed in the subsequent reactions as a solution of the crudematerial, i.e. without further isolation and purification.

If expedient, further compounds of formula (I) according to theinvention can also be prepared by transformations of functional groupsof individual substituents, in particular those listed under R¹ and R⁵,starting with other compounds of formula (I) obtained by the aboveprocesses. These trans-formations are carried out according to customarymethods known to the person skilled in the art and include, for example,reactions such as nucleophilic or electrophilic substitution reactions,transition metal-mediated coupling reactions (for example Suzuki or Heckreactions), oxidation, reduction, hydrogenation, halogenation,alkylation, acylation, amination, hydroxylation, etherification,esterification, ester cleavage and ester hydrolysis, formation ofnitriles, carboxamides and carbamates, and also the introduction andremoval of temporary protective groups.

For example, a compound of the formula (I-B1)

wherein D¹, E, R¹ and R² have the meanings described above,may be converted into the bromo derivative of formula (XVIII)

wherein D¹, E, R¹ and R² have the meanings described above,by treatment with N-bromosuccinimide and then reacted with an alcohol(R—OH) or amine (R—NH—R′) component in the presence of a base to yieldsubstituted analogs of formula (I-B2) and (I-B3), respectively,

wherein D¹, E, R¹ and R² have the meanings described above,andR and R′ represent optionally substituted (C₁-C₄)-alkyl groups asdefined above in the R⁵ section.

The compounds of formula (II) are known from the literature or can beprepared from readily available starting materials by adaptation ofstandard methods described in the literature [see, for example, G. Luoet al., J. Org. Chem. 71, 5392 (2006), and procedures described in WO2007/124288-A1, WO 2005/056550-A2, US 2005/0227968-A1 and EP 1 510516-A1]. In one synthetic route, the parent indazolyl aldehyde offormula (XIX)

wherein R² has the meaning described above,is first halogenated in 3-position and converted into the di-protectedderivative of formula (XX)

wherein PG^(B) and R² have the meanings described above,

-   X represents chloro, bromo or iodo,    and-   R¹⁴ represents (C₁-C₄)-alkyl, or both R¹⁴ residues together form a    —(CH₂)₂— or —(CH₂)₃— bridge,    using standard procedures, and the compound of formula (XX) is then    coupled by means of a suitable transition metal catalyst, preferably    employing copper or palladium catalysts, either-   [C] with a compound of formula (XXI)

R^(1A)—H  (XXI),

-   -   wherein    -   R^(1A) represents an N- or O-linked R¹ residue of the formula        —NR^(9A)R^(9B) or —OR¹⁰, respectively, as defined above,    -   to yield a compound of formula (XXII-A)

-   -   wherein PG^(B), R^(1A), R² and R¹⁴ have the meanings described        above,        or

-   [D] with a compound of formula (XXIII)

R^(1B)-Q  (XXIII),

-   -   wherein    -   R^(1B) represents an optionally substituted C-linked R¹ residue        selected from the group consisting of (C₁-C₆)-alkyl,        (C₃-C₇)-cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl,        5- to 10-membered heteroaryl and benzo-1,4-dioxanyl, as defined        above,    -   and    -   Q represents a —B(OR¹⁵)₂, —MgHal, —ZnHal or —Sn(R¹⁶)₃ group,        wherein        -   Hal is halogen, especially chloro, bromo or iodo,        -   R¹⁵ is hydrogen or (C₁-C₄)-alkyl, or both R¹⁵ residues            together form a —(CH₂)₂—, —C(CH₃)₂—C(CH₃)₂—, —(CH₂)₃— or            —CH₂—C(CH₃)₂—CH₂— bridge,        -   and        -   R¹⁶ is (C₁-C₄)-alkyl,    -   to afford a compound of formula (XXII-B)

-   -   wherein PG^(B), R^(1B), R² and R¹⁴ have the meanings described        above,        and finally the protecting groups are sequentially or        simultaneously removed using standard methods to give the        3-substituted indazolyl aldehydes of formula (II-A) and (II-B),        respectively,

wherein R^(1A), R^(1B) and R² have the meanings described above.

Inert solvents suitable for process steps (XX)+(XXI) (XXII-A) and(XX)+(XXIII)→(XXII-B) include, for example, aromatic hydrocarbons suchas benzene, toluene and xylene, ethers such as diethyl ether,diisopropyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane,tetrahydrofuran, 1,4-dioxane and bis-(2-methoxyethyl)-ether, ordipolar-aprotic solvents such as acetonitrile, dimethylsulfoxide (DMSO),N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA),N-methylpyrrolidinone (NMP), N,N′-dimethylpropylene urea (DMPU) andpyridine. Employing mixtures of these solvents is also possible.Preferred solvents are toluene, tetrahydrofuran, 1,4-dioxane,N,N-dimethylformamide and mixtures thereof.

The coupling reactions (XX)+(XXI)→(XXII-A) and (XX)+(XXIII)→(XXII-B) arecarried out with the aid of a transition metal catalyst. Suitable forthis purpose are in particular copper catalysts such as copper(I)iodide, and palladium catalysts such as palladium on activated charcoal,bis(dibenzylideneacetone)-palladium(0),tris(dibenzylideneacetone)-dipalladium(0),tetrakis(triphenylphosphine)-palladium(0), palladium(II) acetate,bis(triphenylphosphine)-palladium(II) chloride,bis(acetonitrile)-palladium(II) chloride or[1,1′-bis(diphenylphosphino)ferrocene]-palladium(II) chloride,optionally in combination with additional phosphane ligands such as, forexample,dicyclohexyl[2′,4′,6′-tris(1-methylethyl)biphenyl-2-yl]phosphane (XPHOS)or 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) [see, forexample, J. Hassan et al., Chem. Rev. 102, 1359-1469 (2002); V. Farina,V. Krishnamurthy and W. J. Scott, in: The Stille Reaction, Wiley, NewYork, 1998].

Process steps (XX)+(XXI)→(XXII-A) and (XX)+(XXIII)→(XXII-B) are usuallyperformed at a temperature range from +20° C. to +200° C., preferablyfrom +80° C. to +180° C., at atmospheric pressure. However, it is alsopossible to run these reactions at elevated pressure or at reducedpressure (for example in a range from 0.5 to 5 bar). Furthermore, saidtransformations can advantageously be carried out by means ofconcomitant microwave irradiation.

Alternatively, such indazole coupling reactions may be carried out at alater stage in the preparation process, employing compounds of formula(I-A) or (I-C), for example, as precursors wherein R¹ is chloro or bromo[see reaction scheme 6 below]. The reaction parameters described abovefor transformations (XX)+(XXI)→(XXII-A) and (XX)+(XXIII)→(XXII-B), suchas solvents and catalysts, are applied analogously. In some cases,depending on specific reaction conditions and reagents, these couplingreactions can be carried out directly, i.e. without prior protection ofthe indazole N¹-nitrogen.

The compounds of the formulae (BI), (V), (VII), (VIII), (XI), (XIV),(XVI), (XIX), (XXI) and (XXIII) are either commercially available, knownfrom the literature, or can be prepared from readily available startingmaterials by adaptation of standard methods described in the literature.

The preparation of the compounds of the invention can be illustrated bymeans of the following synthesis schemes 1-6. More detailed proceduresare presented below in the experimental section describing the Examples.

Methods of Use

The compounds of the present invention may be used to inhibit theactivity or expression of receptor tyrosine kinases, particularly of thec-Met receptor tyrosine kinase. Moreover, the compounds of the presentinvention exhibit favorable in-vitro clearance properties in livermicrosomes and/or hepatocytes. Therefore, the compounds of formula (I)are expected to be valuable as therapeutic agents.

Accordingly, in another embodiment, the present invention provides amethod of treating disorders relating to or mediated by c-Met kinaseactivity in a patient in need of such treatment, comprisingadministering to the patient an effective amount of a compound offormula (I) as defined above. In certain embodiments, the disordersrelating to c-Met kinase activity are cell proliferative disorders,particularly cancer.

The term “treating” or “treatment” as stated throughout this document isused conventionally, e.g., the management or care of a subject for thepurpose of combating, alleviating, reducing, relieving, improving thecondition of a disease or disorder, such as a carcinoma.

The term “subject” or “patient” includes organisms which are capable ofsuffering from a cell proliferative disorder or who could otherwisebenefit from the administration of a compound of the invention, such ashuman and non-human animals. Preferred humans include human patientssuffering from or prone to suffering from a cell proliferative disorderor associated state, as described herein. The term “non-human animals”includes vertebrates, e.g., mammals, such as non-human primates, sheep,cow, dog, cat and rodents, e.g., mice, and non-mammals, such aschickens, amphibians, reptiles, etc.

The term “disorders relating to or mediated by c-Met” shall includediseases associated with or implicating c-Met activity, for example thehyperactivity of c-Met, and conditions that accompany with thesediseases. Examples of “disorders relating to or mediated by c-Met”include disorders resulting from overstimulation of c-Met due toabnormally high amount of c-Met or mutations in c-Met, or disordersresulting from abnormally high amount of c-Met activity due toabnormally high amount of c-Met or mutations in c-Met.

The term “hyperactivity of c-Met” refers to either c-Met expression incells which normally do not express c-Met or c-Met activity by cellswhich normally do not possess active c-Met or increased c-Met expressionleading to unwanted cell proliferation or mutations leading toconstitutive activation of c-Met.

The term “cell proliferative disorder” includes disorders involving theundesired or uncontrolled proliferation of a cell. The compounds of thepresent invention can be utilized to prevent, inhibit, block, reduce,decrease, control, etc., cell proliferation and/or cell division, and/orproduce apoptosis. This method comprises administering to a subject inneed thereof, including a mammal, including a human, an amount of acompound of this invention, or a pharmaceutically acceptable salt,isomer, polymorph, metabolite, hydrate or solvate thereof which iseffective to treat or prevent the disorder.

Cell proliferative or hyper-proliferative disorders in the context ofthis invention include, but are not limited to, e.g., psoriasis, keloidsand other hyperplasias affecting the skin, endometriosis, skeletaldisorders, angiogenic or blood vessel proliferative disorders, pulmonaryhypertension, fibrotic disorders, mesangial cell proliferativedisorders, colonic polyps, polycystic kidney disease, benign prostatehyperplasia (BPH), and solid tumors, such as cancers of the breast,respiratory tract, brain, reproductive organs, digestive tract, urinarytract, eye, liver, skin, head and neck, thyroid, parathyroid, and theirdistant metastases. Those disorders also include lymphomas, sarcomas andleukemias.

Examples of breast cancer include, but are not limited to invasiveductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ,and lobular carcinoma in situ.

Examples of cancers of the respiratory tract include, but are notlimited to small-cell and non-small-cell lung carcinoma, as well asbronchial adenoma and pleuropulmonary blastoma.

Examples of brain cancers include, but are not limited to brain stem andhypophtalmic glioma, cerebellar and cerebral astrocytoma, glioblastoma,medulloblastoma, ependymoma, as well as neuroectodermal and pinealtumor.

Tumors of the male reproductive organs include, but are not limited toprostate and testicular cancer. Tumors of the female reproductive organsinclude, but are not limited to endometrial, cervical, ovarian, vaginaland vulvar cancer, as well as sarcoma of the uterus.

Tumors of the digestive tract include, but are not limited to anal,colon, colorectal, esophageal, gallbladder, gastric, pancreatic, rectal,small-intestine, and salivary gland cancers.

Tumors of the urinary tract include, but are not limited to bladder,penile, kidney, renal pelvis, ureter, urethral, and hereditary andsporadic papillary renal cancers.

Eye cancers include, but are not limited to intraocular melanoma andretinoblastoma.

Examples of liver cancers include, but are not limited to hepatocellularcarcinoma (liver cell carcinomas with or without fibrolamellar variant),cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixedhepatocellular cholangiocarcinoma.

Skin cancers include, but are not limited to squamous cell carcinoma,Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, andnon-melanoma skin cancer.

Head-and-neck cancers include, but are not limited to laryngeal,hypopharyngeal, nasopharyngeal, oropharyngeal cancer, lip and oralcavity cancer, and squamous cell cancer.

Lymphomas include, but are not limited to AIDS-related lymphoma,non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Burkitt lymphoma,Hodgkin's disease, and lymphoma of the central nervous system.

Sarcomas include, but are not limited to sarcoma of the soft tissue,osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, andrhabdomyosarcoma.

Leukemias include, but are not limited to acute myeloid leukemia, acutelymphoblastic leukemia, chronic lymphocytic leukemia, chronicmyelogenous leukemia, and hairy cell leukemia.

Fibrotic proliferative disorders, i.e. the abnormal formation ofextracellular matrices, that may be treated with the compounds andmethods of the present invention include lung fibrosis, atherosclerosis,restenosis, hepatic cirrhosis, and mesangial cell proliferativedisorders, including renal diseases such as glomerulonephritis, diabeticnephropathy, malignant nephrosclerosis, thrombotic microangiopathysyndromes, transplant rejection, and glomerulopathies.

Other conditions in humans or other mammals that may be treated byadministering a compound of the present invention include tumor growth,retinopathy, including diabetic retinopathy, ischemic retinal-veinocclusion, retinopathy of prematurity and age-related maculardegeneration, rheumatoid arthritis, psoriasis, and bullous disordersassociated with subepidermal blister formation, including bullouspemphigoid, erythema multiforme and dermatitis herpetiformis.

The compounds of the present invention may also be used to prevent andtreat diseases of the airways and the lung, diseases of thegastrointestinal tract as well as diseases of the bladder and bile duct.

The disorders mentioned above have been well characterized in humans,but also exist with a similar etiology in other animals, includingmammals, and can be treated by administering pharmaceutical compositionsof the present invention.

Compounds of formula (I) may be administered as the sole pharmaceuticalagent or in combination with one or more additional therapeutic agentswhere the combination causes no unacceptable adverse effects. Thiscombination therapy includes administration of a single pharmaceuticaldosage formulation which contains a compound of formula (I) and one ormore additional therapeutic agents, as well as administration of thecompound of formula (I) and each additional therapeutic agent in its ownseparate pharmaceutical dosage formulation. For example, a compound offormula (I) and a therapeutic agent may be administered to the patienttogether in a single oral dosage composition such as a tablet orcapsule, or each agent may be administered in separate dosageformulations.

Where separate dosage formulations are used, the compound of formula (I)and one or more additional therapeutic agents may be administered atessentially the same time (e.g., concurrently) or at separatelystaggered times (e.g., sequentially).

In particular, the compounds of the present invention may be used infixed or separate combination with other anti-tumor agents such asalkylating agents, anti-metabolites, plant-derived anti-tumor agents,hormonal therapy agents, topoisomerase inhibitors, camptothecinderivatives, kinase inhibitors, targeted drugs, antibodies, interferonsand/or biological response modifiers, anti-angiogenic compounds, andother anti-tumor drugs. In this regard, the following is a non-limitinglist of examples of secondary agents that may be used in combinationwith the compounds of the present invention:

-   -   Alkylating agents include, but are not limited to, nitrogen        mustard N-oxide, cyclophosphamide, ifosfamide, thiotepa,        ranimustine, nimustine, temozolomide, altretamine, apaziquone,        brostallicin, bendamustine, carmustine, estramustine,        fotemustine, glufosfamide, mafosfamide, bendamustin, and        mitolactol; platinum-coordinated alkylating compounds include,        but are not limited to, cisplatin, carboplatin, eptaplatin,        lobaplatin, nedaplatin, oxaliplatin, and satraplatin;    -   Anti-metabolites include, but are not limited to, methotrexate,        6-mercaptopurine riboside, mercaptopurine, 5-fluorouracil alone        or in combination with leucovorin, tegafur, doxifluridine,        carmofur, cytarabine, cytarabine ocfosfate, enocitabine,        gemcitabine, fludarabin, 5-azacitidine, capecitabine,        cladribine, clofarabine, decitabine, eflornithine,        ethynylcytidine, cytosine arabinoside, hydroxyurea, melphalan,        nelarabine, nolatrexed, ocfosfite, disodium premetrexed,        pentostatin, pelitrexol, raltitrexed, triapine, trimetrexate,        vidarabine, vincristine, and vinorelbine;    -   Hormonal therapy agents include, but are not limited to,        exemestane, Lupron, anastrozole, doxercalciferol, fadrozole,        formestane, 11-beta hydroxysteroid dehydrogenase 1 inhibitors,        17-alpha hydroxylase/17,20 lyase inhibitors such as abiraterone        acetate, 5-alpha reductase inhibitors such as fmasteride and        epristeride, anti-estrogens such as tamoxifen citrate and        fulvestrant, Trelstar, toremifene, raloxifene, lasofoxifene,        letrozole, anti-androgens such as bicalutamide, flutamide,        mifepristone, nilutamide, Casodex, and anti-progesterones and        combinations thereof;    -   Plant-derived anti-tumor substances include, e.g., those        selected from mitotic inhibitors, for example epothilones such        as sagopilone, ixabepilone and epothilone B, vinblastine,        vinflunine, docetaxel, and paclitaxel;    -   Cytotoxic topoisomerase inhibiting agents include, but are not        limited to, aclarubicin, doxorubicin, amonafide, belotecan,        camptothecin, 10-hydroxycamptothecin, 9-aminocamptothecin,        diflomotecan, irinotecan, topotecan, edotecarin, epimbicin,        etoposide, exatecan, gimatecan, lurtotecan, mitoxantrone,        pirambicin, pixantrone, rubitecan, sobuzoxane, tafluposide, and        combinations thereof;    -   Immunologicals include interferons such as interferon alpha,        interferon alpha-2a, interferon alpha-2b, interferon beta,        interferon gamma-1a and interferon gamma-n1, and other immune        enhancing agents such as L19-IL2 and other IL2 derivatives,        filgrastim, lentinan, sizofilan, TheraCys, ubenimex,        aldesleukin, alemtuzumab, BAM-002, dacarbazine, daclizumab,        denileukin, gemtuzumab, ozogamicin, ibritumomab, imiquimod,        lenograstim, lentinan, melanoma vaccine (Corixa), molgramostim,        sargramostim, tasonermin, tecleukin, thymalasin, tositumomab,        Vimlizin, epratuzumab, mitumomab, oregovomab, pemtumomab, and        Provenge;    -   Biological response modifiers are agents that modify defense        mechanisms of living organisms or biological responses such as        survival, growth or differentiation of tissue cells to direct        them to have anti-tumor activity; such agents include, e.g.,        krestin, lentinan, sizofuran, picibanil, ProMune, and ubenimex;    -   Anti-angiogenic compounds include, but are not limited to,        acitretin, aflibercept, angiostatin, aplidine, asentar,        axitinib, bevacizumab, brivanib alaninat, cilengtide,        combretastatin, endostatin, fenretinide, halofuginone,        pazopanib, ranibizumab, rebimastat, recentin, regorafenib,        removab, revlimid, sorafenib, squalamine, sunitinib, telatinib,        thalidomide, ukrain, vatalanib, and vitaxin;    -   Antibodies include, but are not limited to, trastuzumab,        cetuximab, bevacizumab, rituximab, ticilimumab, ipilimumab,        lumiliximab, catumaxomab, atacicept, oregovomab, and        alemtuzumab;    -   VEGF inhibitors such as, e.g., sorafenib, regorafenib,        bevacizumab, sunitinib, recentin, axitinib, aflibercept,        telatinib, brivanib alaninate, vatalanib, pazopanib, and        ranibizumab;    -   EGFR (HERO inhibitors such as, e.g., cetuximab, panitumumab,        vectibix, gefitinib, erlotinib, and Zactima;    -   HER2 inhibitors such as, e.g., lapatinib, tratuzumab, and        pertuzumab;    -   mTOR inhibitors such as, e.g., temsirolimus,        sirolimus/Rapamycin, and everolimus;    -   c-Met inhibitors;    -   PI3K and AKT inhibitors;    -   CDK inhibitors such as roscovitine and flavopiridol;    -   Spindle assembly checkpoints inhibitors and targeted        anti-mitotic agents such as PLK inhibitors, Aurora inhibitors        (e.g. Hesperadin), checkpoint kinase inhibitors, and KSP        inhibitors;    -   HDAC inhibitors such as, e.g., panobinostat, vorinostat, MS275,        belinostat, and LBH589;    -   HSP90 and HSP70 inhibitors;    -   Proteasome inhibitors such as bortezomib and carfilzomib;    -   Serine/threonine kinase inhibitors including MEK inhibitors and        Raf inhibitors such as sorafenib;    -   Farnesyl transferase inhibitors such as, e.g., tipifarnib;    -   Tyrosine kinase inhibitors including, e.g., dasatinib,        nilotibib, regorafenib, bosutinib, sorafenib, bevacizumab,        sunitinib, cediranib, axitinib, aflibercept, telatinib, imatinib        mesylate, brivanib alaninate, pazopanib, ranibizumab, vatalanib,        cetuximab, panitumumab, vectibix, gefitinib, erlotinib,        lapatinib, tratuzumab, pertuzumab, and c-Kit inhibitors;    -   Vitamin D receptor agonists;    -   Bcl-2 protein inhibitors such as obatoclax, oblimersen sodium,        and gossypol;    -   Cluster of differentiation 20 receptor antagonists such as,        e.g., rituximab;    -   Ribonucleotide reductase inhibitors such as, e.g., gemcitabine;    -   Tumor necrosis apoptosis inducing ligand receptor 1 agonists        such as, e.g., mapatumumab;    -   5-Hydroxytryptamine receptor antagonists such as, e.g., rEV598,        xaliprode, palonosetron hydrochloride, granisetron, Zindol, and        AB-1001;    -   Integrin inhibitors including alpha5-beta1 integrin inhibitors        such as, e.g., E7820, JSM 6425, volociximab, and endostatin;    -   Androgen receptor antagonists including, e.g., nandrolone        decanoate, fluoxymesterone, Android, Prost-aid, andromustine,        bicalutamide, flutamide, apo-cyproterone, apo-flutamide,        chlormadinone acetate, Androcur, Tabi, cyproterone acetate, and        nilutamide;    -   Aromatase inhibitors such as, e.g., anastrozole, letrozole,        testolactone, exemestane, aminoglutethimide, and formestane;    -   Matrix metalloproteinase inhibitors;    -   Other anti-cancer agents including, e.g., alitretinoin,        ampligen, atrasentan bexarotene, bortezomib, bosentan,        calcitriol, exisulind, fotemustine, ibandronic acid,        miltefosine, mitoxantrone, I-asparaginase, procarbazine,        dacarbazine, hydroxycarbamide, pegaspargase, pentostatin,        tazaroten, velcade, gallium nitrate, canfosfamide, darinaparsin,        and tretinoin.

In a preferred embodiment, the compounds of the present invention may beused in combination with chemotherapy (i.e. cytotoxic agents),anti-hormones and/or targeted therapies such as other kinase inhibitors(for example, EGFR inhibitors), mTOR inhibitors and angiogenesisinhibitors.

The compounds of the present invention may also be employed in cancertreatment in conjunction with radiation therapy and/or surgicalintervention.

Furthermore, the compounds of formula (I) may be utilized, as such or incompositions, in research and diagnostics, or as analytical referencestandards, and the like, which are well known in the art.

Pharmaceutical Compositions and Methods of Treatment

In another aspect, the invention provides a pharmaceutical compositioncomprising a compound of formula (I) as defined above, together with apharmaceutically acceptable carrier.

In still another aspect, the invention provides a process for preparinga pharmaceutical composition. The process includes the step ofcomprising combining at least one compound of formula (I) as definedabove with at least one pharmaceutically acceptable carrier, andbringing the resulting combination into a suitable administration form.

The active component of formula (I) can act systemically and/or locally.For this purpose, it can be applied in a suitable manner, for exampleorally, parenterally, pulmonally, nasally, sublingually, lingually,buccally, rectally, transdermally, conjunctivally, otically, or as animplant or stent.

For these application routes, the active component of formula (I) can beadministered in suitable application forms.

Useful oral application forms include application forms which releasethe active component rapidly and/or in modified form, such as, forexample, tablets (non-coated and coated tablets, for example with anenteric coating), capsules, sugar-coated tablets, granules, pellets,powders, emulsions, suspensions, solutions and aerosols.

Parenteral application can be carried out with avoidance of anabsorption step (intravenously, intraarterially, intracardially,intraspinally or intralumbarly) or with inclusion of an absorption(intramuscularly, subcutaneously, intracutaneously, percutaneously orintraperitoneally). Useful parenteral application forms includeinjection and infusion preparations in the form of solutions,suspensions, emulsions, lyophilisates and sterile powders.

Forms suitable for other application routes include, for example,inhalatory pharmaceutical forms (including powder inhalers, nebulizers),nasal drops, solutions or sprays, tablets or capsules to be administeredlingually, sublingually or buccally, suppositories, ear and eyepreparations, vaginal capsules, aqueous suspensions (lotions, shakemixtures), lipophilic suspensions, ointments, creams, milk, pastes,dusting powders, implants or stents.

In a preferred embodiment, the pharmaceutical composition comprising acompound of formula (I) as defined above is provided in a form suitablefor oral administration. In another preferred embodiment, thepharmaceutical composition comprising a compound of formula (I) asdefined above is provided in a form suitable for intravenousadministration.

The active component of formula (I) can be converted into the recitedapplication forms in a manner known per se. This is carried out usinginert non-toxic, pharmaceutically suitable excipients. These include,inter alfa, carriers (for example microcrystalline cellulose), solvents(for example liquid polyethylene glycols), emulsifiers (for examplesodium dodecyl sulphate), dispersing agents (for examplepolyvinylpyrrolidone), synthetic and natural biopolymers (for examplealbumin), stabilizers (for example antioxidants such as ascorbic acid),colorants (for example inorganic pigments such as iron oxides) or tasteand/or odor corrigents.

In another embodiment, the invention provides a method of treating acell proliferative disorder in a patient in need of such treatment,comprising administering to the patient an effective amount of acompound of formula (I) as defined above. In certain embodiments, thecell proliferative disorder is cancer.

In still another aspect, the invention provides use of a compound offormula (I) as defined above for manufacturing a pharmaceuticalcomposition for the treatment or prevention of a cell proliferativedisorder. In certain embodiments, the cell proliferative disorder iscancer.

When the compounds of the present invention are administered aspharmaceuticals, to humans and animals, they can be given per se or as apharmaceutical composition containing, for example, 0.1 to 99.5% (morepreferably, 0.5 to 90%) of active ingredient in combination with apharmaceutically-acceptable carrier.

Regardless of the route of administration selected, the compounds of theinvention, which may be used in a suitable hydrated form, and/or thepharmaceutical compositions of the present invention, are formulatedinto pharmaceutically-acceptable dosage forms by conventional methodsknown to those of skill in the art.

Actual dosage levels and time course of administration of the activeingredients in the pharmaceutical compositions of the invention may bevaried so as to obtain an amount of the active ingredient which iseffective to achieve the desired therapeutic response for a particularpatient, composition, and mode of administration, without being toxic tothe patient. An exemplary dose range is from 0.01 to 100 mg/kg per dayor 0.1 to 150 mg/kg per day.

In certain embodiments, the compound of the invention can be used incombination therapy with conventional cancer chemotherapeutics.Conventional treatment regimens for leukemia and for other tumorsinclude radiation, drugs, or a combination of both.

Determination of a therapeutically effective anti-proliferative amountor a prophylactically effective anti-proliferative amount of thecompounds of the invention can be readily made by the physician orveterinarian (the “attending clinician”), as one skilled in the art, bythe use of known techniques and by observing results obtained underanalogous circumstances. The dosages may be varied depending upon therequirements of the patient in the judgment of the attending clinician;

the severity of the condition being treated and the particular compoundbeing employed. In determining the therapeutically effectiveanti-proliferative amount or dose, and the prophylactically effectiveanti-proliferative amount or dose, a number of factors are considered bythe attending clinician, including, but not limited to: the specificcell proliferative disorder involved; pharmacodynamic characteristics ofthe particular agent and its mode and route of administration; thedesired time course of treatment; the species of mammal; its size, age,and general health; the specific disease involved; the degree of orinvolvement or the severity of the disease; the response of theindividual patient; the particular compound administered; the mode ofadministration; the bioavailability characteristics of the preparationadministered; the dose regimen selected; the kind of concurrenttreatment (i.e., the interaction of the compound of the invention withother co-administered therapeutics); and other relevant circumstances.

Treatment can be initiated with smaller dosages, which are less than theoptimum dose of the compound. Thereafter, the dosage may be increased bysmall increments until the optimum effect under the circumstances isreached. For convenience, the total daily dosage may be divided andadministered in portions during the day if desired. A therapeuticallyeffective anti-proliferative amount and a prophylactically effectiveanti-proliferative amount of a compound of the invention may be expectedto vary from about 0.01 milligram per kilogram of body weight per day(mg/kg/day) to about 100 mg/kg/day.

A preferred dose of the compound of the invention for the presentinvention is the maximum that a patient can tolerate and not developserious side effects. Illustratively, the compound of the presentinvention is administered at a dose of about 0.01 mg/kg to about 100mg/kg of body weight, about 0.01 mg/kg to about 10 mg/kg of body weightor about 0.1 mg/kg to about 10 mg/kg of body weight. Ranges intermediateto the above-recited values are also intended to be part of theinvention.

The percentages in the tests and examples which follows are, unlessotherwise stated, by weight; parts are by weight. Solvent ratios,dilution ratios and concentrations reported for liquid/liquid solutionsare each based on volume.

A. EXAMPLES Abbreviations and Acronyms

-   Ac acetyl-   aq. aqueous (solution)-   br. s broad singlet (NMR)-   conc. concentrated-   d doublet (NMR)-   DCI direct chemical ionization (MS)-   dd doublet of doublets (NMR)-   DMF N,N-dimethylformamide-   DMSO dimethylsulfoxide-   DMSO-d₆ dimethylsulfoxide-d₆-   ee enantiomeric excess-   EI electron impact ionization (MS)-   equiv. equivalent(s)-   ESI electro-spray ionization (MS)-   Et ethyl-   EtOAc ethyl acetate-   GC-MS gas chromatography-coupled mass spectrometry-   h hour(s)-   ¹H-NMR proton nuclear magnetic resonance spectrometry-   HOAc acetic acid-   HPLC high performance/high pressure liquid chromatography-   LC-MS liquid chromatography-coupled mass spectrometry-   m multiplet (NMR)-   Me methyl-   MeOH methanol-   min minute(s)-   MS mass spectrometry-   m/z mass-to-charge ratio-   of th. of theory (chemical yield)-   Ph phenyl-   q quartet (NMR)-   R_(f) TLC retention factor-   RP reverse phase (HPLC)-   rt room temperature-   R_(t) retention time (HPLC)-   singlet (NMR)-   tBu tert-butyl-   tBuO tert-butoxy-   TFA trifluoroacetic acid-   THF tetrahydrofuran-   TLC thin layer chromatography-   t triplet (NMR)-   v/v volume-to-volume ratio-   w/v weight-to-volume ratio-   w/w weight-to-weight ratio

LC-MS and GC-MS Methods: Method 1 (LC-MS):

Instrument: Micromass ZQ with HPLC Waters Alliance 2795; column:Phenomenex Synergi 2.5μ MAX-RP 100A Mercury, 20 mm×4 mm; eluent A: 1 Lwater+0.5 mL 50% formic acid, eluent B: 1 L acetonitrile+0.5 mL 50%formic acid; gradient: 0.0 min 90% A→0.1 min 90% A→3.0 min 5% A→4.0 min5% A→4.01 min 90% A; flow rate: 2 mL/min; oven: 50° C.; UV detection:210 nm.

Method 2 (LC-MS):

Instrument: Micromass Quattro Premier with HPLC Waters HPLC Acquity;column: Thermo Hypersil GOLD 1.9μ, 50 mm×1 mm; eluent A: 1 L water+0.5mL 50% formic acid, eluent B: 1 L acetonitrile+0.5 mL 50% formic acid;gradient: 0.0 min 90% A→0.1 min 90% A→1.5 min 10% A→2.2 min 10% A; oven:50° C.; flow rate: 0.33 mL/min; UV detection: 210 nm.

Method 3 (GC-MS):

Instrument: Micromass GCT, GC6890; column: Restek RTX-35, 15 m×200μm×0.33 μm; constant flow with helium: 0.88 mL/min; oven: 70° C.; inlet:250° C.; gradient: 70° C., 30° C./min→310° C. (keep for 3 min).

Method 4 (LC-MS):

Instrument: Waters Acquity SQD HPLC System; column: Waters Acquity HPLCHSS T3 1.8μ, 50 mm×1 mm; eluent A: 1 L water+0.25 mL 99% formic acid,eluent B: 1 L acetonitrile+0.25 mL 99% formic acid; gradient: 0.0 min90% A→1.2 min 5% A→2.0 min 5% A; oven: 50° C.; flow rate: 0.40 mL/min;UV detection: 210-400 nm.

Method 5 (LC-MS):

Instrument: Micromass Quattro Micro with HPLC Agilent 1100 Series;column: Thermo Hypersil GOLD 3μ, 20 mm×4 mm; eluent A: 1 L water+0.5 mL50% formic acid, eluent B: 1 L acetonitrile+0.5 mL 50% formic acid;gradient: 0.0 min 100% A→3.0 min 10% A→4.0 min 10% A→4.01 min 100% A(flow rate 2.5 mL/min)→5.00 min 100% A; oven: 50° C.; flow rate: 2mL/min; UV detection: 210 nm.

Method 6 (LC-MS):

Instrument: Micromass ZQ with HPLC HP 1100 Series; UV DAD; column:Phenomenex Gemini 3μ, 30 mm×3.00 mm; eluent A: 1 L water+0.5 mL 50%formic acid, eluent B: 1 L acetonitrile+0.5 mL 50% formic acid;gradient: 0.0 min 90% A→2.5 min 30% A→3.0 min 5% A→4.5 min 5% A; flowrate: 0.0 min 1 mL/min→2.5 min/3.0 min/4.5 min 2 mL/min; oven: 50° C.;UV detection: 210 nm.

Starting Materials and Intermediates Example 1A3-Methyl-1H-indazole-5-carbaldehyde

Tetrahydrofuran (600 ml) was cooled down to −78° C. under argonatmosphere. At this temperature, a 1.7 M solution of tert-butyllithiumin n-pentane (200 ml) was added dropwise. After 15 minutes at −78° C., asolution of 22.4 g (106.1 mmol) 5-bromo-3-methyl-1H-indazole in THF (300ml) was added dropwise at such a rate that the temperature of thesolution did not exceed −70° C. The mixture was stirred for 30 minutesbefore N,N-dimethylformamide (24.5 ml) was added dropwise. After 20 min,the cooling bath was removed, and stirring was continued for 1 h beforewater (250 ml) was added carefully. The mixture was extracted severaltimes with ethyl acetate (500 ml). The combined organic layers werewashed with saturated aqueous sodium chloride solution, dried oversodium sulfate, and concentrated under reduced pressure to yield 18.5 gof crude 3-methyl-1H-indazole-5-carbaldehyde, which was used in the nextstep without further purification.

¹H-NMR (DMSO-d₆): δ=13.13 (br. s, 1H), 10.01 (s, 1H), 8.40 (s, 1H), 7.81(d, 1H), 7.58 (d, 1H), 2.56 (s, 3H) ppm.

Example 2A(2E)-2-[(3-Methyl-1H-indazol-5-yl)methylidene]-3-oxobutanenitrile

A mixture of 5.0 g (31.2 mmol) 3-methyl-1H-indazole-5-carbaldehyde(Example 1A), 3.61 g (34.3 mmol) sodium (1Z)-1-cyanoprop-1-en-2-olate,2.23 ml (39 mmol) acetic acid and 0.31 ml (3.12 mmol) piperidine in drydichloromethane (250 ml) containing 4 Å molecular sieve was stirredunder reflux for 12 h. Upon cooling, a precipitate was formed which wascollected by filtration and washed with saturated aqueous sodiumbicarbonate solution and water. The solid was dissolved in ethanol, andthe molecular sieve was filtered off. The filtrate was concentratedunder reduced pressure, and the residue was treated with ethyl acetateand saturated aqueous sodium carbonate solution. The organic layer waswashed with water, dried, and concentrated under reduced pressure toafford the title compound (3.5 g, 50% of th.) as a pale yellow solidwhich was used in the next step without further purification.

LC-MS (method 1): R_(t)=1.32 min; MS (ESIpos): m/z=226 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=13.18 (br. s, 1H), 8.52 (s, 1H), 8.49 (s,1H), 8.19 (d, 1H), 7.69 (d, 1H), 2.55 (br. m, 6H) ppm.

Example 3A 1-(5-Bromo-2-fluorophenyl)-1-propanol

To a solution of 15 g (73.9 mmol) 5-bromo-2-fluorobenzaldehyde indiethyl ether (100 ml) at 0° C. were slowly added 27.1 ml (81.3 mmol) ofethyl magnesium bromide (3 M solution in diethyl ether). After stirringat 0° C. for 3 h, water (20 ml) was carefully added upon which a whiteprecipitate formed. The solid was filtered off and washed withtert-butylmethyl ether. The combined filtrates were washed with brine,dried over sodium sulfate and concentrated under reduced pressure. Thecrude title compound thus obtained (16.1 g, 93% of th.) was used in thenext step without further purification.

GC-MS (method 3): R_(t)=4.54 min; MS (EIpos): m/z=232 (M)⁺.

Example 4A 1-(5-Bromo-2-fluorophenyl)-1-propanone

A mixture of 10 g (42.9 mmol) 1-(5-bromo-2-fluorophenyl)-1-propanol(Example 3A), 8.75 g (85.8 mmol) neutral aluminium oxide and 18.5 g(85.8 mmol) pyridinium chlorochromate in dichloromethane (100 ml) wasstirred at room temperature for 4 h. The mixture was then filteredthrough silica gel (200 g, 0.06-0.2 mm) which was thoroughly washed withdichloromethane (1000 ml). The combined filtrates were washed withbrine, dried over sodium sulfate and concentrated under reducedpressure. The crude title compound thus obtained (8.6 g, 87% of th.) wasused in the next step without further purification.

GC-MS (method 3): R_(t)=4.30 min; MS (EIpos): m/z=230 (M)⁺.

Example 5A 5-Bromo-3-ethyl-1H-indazole

A solution of 7.50 g (32.5 mmol) 1-(5-bromo-2-fluorophenyl)-1-propanone(Example 4A) in 1-methyl-2-pyrrolidone (NMP; 100 ml) was treated with3.25 g (3.16 ml, 64.9 mmol) hydrazine hydrate and stirred at refluxtemperature for 16 h. Upon cooling, the mixture was poured into amixture of ice and water. The precipitate was collected by filtrationand washed thoroughly with water to yield 4.56 g (62% of th.) of thetitle compound as a beige-coloured solid.

LC-MS (method 4): R_(t)=1.00 min; MS (ESIpos): m/z=225 (M+H)⁺.

Example 6A 3-Ethyl-1H-indazole-5-carbaldehyde

A solution of 6.90 g (30.7 mmol) 5-bromo-3-ethyl-1H-indazole (Example5A) in THF (300 ml) was cooled to −78° C. At this temperature, a 1.7 Msolution of tert-butyllithium in n-pentane (63.1 ml, 107 mmol) wasslowly added. The mixture was stirred at −78° C. for 30 minutes beforeN,N-dimethylformamide (80.0 ml) was slowly added. The cooling bath wasremoved, and stirring was continued until room temperature was reached.Then, water (250 ml) was added carefully. The mixture was extractedseveral times with ethyl acetate (500 ml). The combined organic layerswere washed with saturated aqueous sodium chloride solution, dried oversodium sulfate, and concentrated under reduced pressure to yield 4.5 g(84% of th.) of the crude title compound which was used in the next stepwithout further purification.

LC-MS (method 4): R_(t)=0.73 min; MS (ESIpos): m/z=175 (M+H)⁺.

Example 7A(2E)-2-[(3-Ethyl-1H-indazol-5-yl)methylidene]-3-oxobutanenitrile

A mixture of 0.50 g (2.87 mmol) 3-ethyl-1H-indazole-5-carbaldehyde(Example 6A), 0.33 g (3.16 mmol) sodium (1Z)-1-cyanoprop-1-en-2-olate,0.21 ml (3.6 mmol) acetic acid and 0.028 ml (0.29 mmol) piperidine indry dichloromethane (25 ml) containing 4 Å molecular sieve was stirredunder reflux for 16 h. Upon cooling, a precipitate was formed which wascollected by filtration and washed with saturated aqueous sodiumbicarbonate solution and water. The solid was dissolved in ethanol, andthe molecular sieve was filtered off. The filtrate was concentratedunder reduced pressure, and the residue was treated with ethyl acetateand saturated aqueous sodium carbonate solution. The organic layer waswashed with water, dried, and concentrated under reduced pressure toafford the title compound (0.60 g, 88% of th.) as a pale yellow solidwhich was used in subsequent steps without further purification.

LC-MS (method 1): R_(t)=1.50 min; MS (ESIpos): m/z=240 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=13.17 (br. s, 1H), 8.59 (s, 1H), 8.51 (s,1H), 8.17 (d, 1H), 7.67 (d, 1H), 2.97 (q, 2H), 2.55 (br. m, 3H), 1.36(t, 3H) ppm.

Example 8A (2E)-2-(1H-Indazol-5-ylmethylidene)-3-oxobutanenitrile

10 g (68.4 mmol) 1H-indazole-5-carbaldehyde [preparation described in US2005/0227968-A1 (Intermediate 1)], 7.91 g (75.2 mmol) sodium(1Z)-1-cyanoprop-1-en-2-olate, 4.89 ml (85.5 mmol) acetic acid and 0.68ml (6.84 mmol) piperidine in dry dichloromethane (500 ml) were stirredat reflux temperature for 7 h using an inverse water separator. Uponcooling, a precipitate was formed which was collected by filtration andwashed with dichloromethane. The solid was dried in vacuo to afford thecrude title compound (19 g, 75% purity by LC-MS, 96% of th.) which wasused in subsequent steps without further purification.

LC-MS (method 2): R_(t)=0.82 min; MS (ESIpos): m/z=212 (M+H)⁺.

Example 9A 5-Methoxy-3,6-dihydro-2H-1,4-oxazine

A solution of 1.2 g (11.9 mmol) morpholine-3-one in dichloromethane (70ml) was cooled to 0° C. and treated with 25 g (238 mmol) dry sodiumcarbonate. After stirring for 10 min at 0° C., 6.14 g (41.5 mmol)trimethyloxonium tetrafluoroborate were added at 0° C. The mixture wasallowed to warm to room temperature and stirred for 6 h. Water (100 ml)was added, and the organic layer was separated. The aqueous phase wasextracted several times with dichloromethane, and the combined organiclayers were washed with brine, dried over sodium sulfate andconcentrated under reduced pressure. The crude product thus obtained wasused in the next step without further purification.

GC-MS (method 3): R_(t)=3.36 min; MS (ESIpos): m/z=116 (M+H)⁺.

Example 10A tert-Butyl (2E/Z)-cyano(morpholin-3-ylidene)ethanoate

A mixture of 0.48 g (4.17 mmol) 5-methoxy-3,6-dihydro-2H-1,4-oxazine(Example 9A) and 0.61 g (4.34 mmol) tert-butyl cyanoacetate in THF (25ml) was stirred under reflux for 12 h. The mixture was then cooled toroom temperature and concentrated under reduced pressure. The residuewas purified by flash chromatography (silica gel, eluentcyclohexane/ethyl acetate 3:1) to yield the title compound as a whitesolid (0.269 g, 27% of th.).

LC-MS (method 2): R_(t)=0.99 min; MS (ESIpos): m/z=225 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=10.02 (br. s, 1H), 4.47 (s, 2H), 3.84 (t,2H), 3.37 (m, 2H), 1.44 (s, 9H) ppm.

Example 11A 3-Amino-3-(6-methoxypyridin-3-yl)prop-2-enenitrile

A solution of 0.258 ml (1.844 mmol) diisopropylamine in dry THF (1.5 ml)was cooled to −70° C. under inert gas atmosphere, and 1.152 ml (1.844mmol) n-butyllithium (1.6 M solution in hexanes) were added dropwise.Then, a solution of 85.6 μl (1.627 mmol) acetonitrile in dry THF (1.5ml) was slowly added over 10 min. The resulting solution was stirred forfurther 30 min at −70° C. before a solution of 150 mg (1.085 mmol)2-methoxypyridine-5-carbonitrile in dry THF (1.5 ml) was added. Themixture was allowed to warm to room temperature and stirred for 1 hbefore water (2 ml) was added slowly. The mixture was extracted severaltimes with dichloromethane (50 ml). The combined organic layers weredried over sodium sulfate and concentrated under reduced pressure toyield 188 mg (99% of th.) of the crude title compound which was used inthe next step without further purification.

GC-MS (method 3): R_(t)=6.45 min; MS (EIpos): m/z=175 (M)⁺.

Example 12A 5-Methoxy-3-oxopentanenitrile

A flame-dried flask was charged with 5 ml (8.0 mmol) n-butyllithium (1.6M solution in hexanes) in dry THF (25 ml) under inert gas atmosphere andcooled to −78° C. Next, 0.368 ml (7 mmol) acetonitrile were slowlyadded, and the resulting mixture was stirred for 1 h at −70° C. Then,0.585 ml (5.0 mmol) methyl 3-methoxypropanoate were slowly addedmaintaining the temperature below −66° C. The reaction mixture wasstirred for 2 h at −45° C. and then quenched by addition of hydrochloricacid (2 M, 16 ml) keeping the temperature below −35° C. The resultingclear solution was allowed to warm to room temperature and thenconcentrated under reduced pressure, and the residue was dried underhigh vacuum. The crude product thus obtained (1.51 g) was used in thenext step without further purification.

GC-MS (method 3): R_(t)=3.18 min; MS (EIpos): m/z=127 (M)⁺.

Example 13A 3-Bromo-1H-indazole-5-carbaldehyde

To a solution of 20 g (137 mmol) 1H-indazole-5-carbaldehyde inacetonitrile (580 ml), 28 g (157 mmol) 1-bromopyrrolidine-2,5-dione wereadded over 20 min at room temperature. The resulting suspension wasstirred under reflux for 30 min, then cooled to room temperature andconcentrated under reduced pressure. The residue was dissolved in ethylacetate (1500 ml), and the solution was washed with water and withbrine, dried over sodium sulfate, filtered and concentrated underreduced pressure. The crude product was triturated with ethyl acetate.After filtration, the precipitate was dried under vacuum to yield thetitle compound as a white solid (30.9 g, 75% of th.).

LC-MS (method 4): R_(t)=0.77 min; MS (ESIpos): m/z=225 (M+H)⁺¹H-NMR (400MHz, DMSO-d₆): δ=15.01 (br. s, 1H), 10.09 (s, 1H), 8.29 (s, 1H), 7.91(d, 1H), 7.73 (d, 1H) ppm.

Example 14A 3-Amino-3-(4-chloro-3-fluorophenyl)prop-2-enenitrile

The title compound was prepared following the procedure described forExample 11A using 4-chloro-3-fluorobenzonitrile (300 mg, 1.85 mmol) toyield 358 mg (98% of th.) of the crude product which was used in thenext step without further purification.

GC-MS (method 3): R_(t)=6.30 min; MS (EIpos): m/z=196 (M)⁺.

Example 15A 3-Amino-3-(3,5-difluorophenyl)prop-2-enenitrile

The title compound was prepared following the procedure described forExample 11A using 3,5-difluorobenzonitrile (500 mg, 3.59 mmol) to yield640 mg (99% of th.) of the crude product which was used in the next stepwithout further purification.

GC-MS (method 3): R_(t)=5.13 min; MS (EIpos): m/z=180 (M)⁺.

Example 16A 3-Amino-3-(2,4-difluorophenyl)prop-2-enenitrile

The title compound was prepared following the procedure described forExample 11A using 2,4-difluorobenzonitrile (300 mg, 2.1 mmol) to yield288 mg (76% of th.) of the crude product which was used in the next stepwithout further purification.

GC-MS (method 3): R_(t)=5.13 min; MS (EIpos): m/z=180 (M)⁺.

Example 17A 6-Fluoro-3-methyl-1H-indazole-5-carbaldehyde

A solution of 30 g (131 mmol) 5-bromo-6-fluoro-3-methyl-1H-indazole[preparation described in WO 2005/085227-A1, Example 104c); alsocommercially available, CAS Reg.-No. 864773-66-0] in THF (525 ml) wascooled to −45° C. A solution of methylmagnesium chloride in THF (3 M;50.2 ml, 151 mmol) was added dropwise at −45° C., and the resultingsolution was stirred for 40 min at this temperature. Using a dosingpump, 253 ml (354 mmol) of 2-butyllithium solution (1.4 M incyclohexane) were added so that the temperature did not exceed −40° C.The resulting mixture was stirred for 30 min at −40° C., and then 30.2ml (393 mmol) N,N-dimethylformamide were added dropwise keeping thetemperature at −40° C. The resulting mixture was stirred for 30 min at−40° C., then allowed to warm up to room temperature, and slowly pouredinto a volume of 2.8 L of 2 N hydrochloric acid cooled to 5° C.(ice-water bath). The mixture was extracted several times with ethylacetate. The combined organic layers were washed with brine, dried oversodium sulfate, filtered, and concentrated under reduced pressure. Theresidue was dissolved in dichloromethane and purified by chromatographyon silica gel (eluent: pentane/ethyl acetate 6:4 v/v) to afford 19.6 g(78% of th.) of the title compound as a pale yellow solid.

MS (ESIpos): m/z=179 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=13.14 (s, 1H), 10.17 (s, 1H), 8.33 (d, 1H),7.37 (d, 1H), 2.54 (s, ³H) ppm.

Example 18A(2E)-2-[(6-Fluoro-3-methyl-1H-indazol-5-yl)methylidene]-3-oxobutanenitrile

Following the procedure described for Example 2A, the title compound wasprepared using 2.74 g (15.5 mmol)6-fluoro-3-methyl-1H-indazole-5-carbaldehyde (Example 17A) and 2.6 g(24.8 mmol) sodium (1Z)-1-cyanoprop-1-en-2-olate to yield 1.6 g (42% ofth.) of the crude product which was used in the next step withoutfurther purification.

LC-MS (method 4): R_(t)=0.83 min; MS (ESIpos): m/z=244 (M+H)⁺.

Example 19A 6-Fluoro-1H-indazole-5-carbaldehyde

A slurry of 4.8 g (30 mmol) 6-fluoro-1H-indazole-5-carbonitrile[commercially available; preparation given in EP 1 510 516-A1(production example 82)] in anhydrous toluene (150 ml) was cooled to−40° C. Under inert gas atmosphere, 48 ml (72 mmol) diisobutylaluminiumhydride solution (1.5 M in toluene) were added over 30 min, and theresulting mixture was stirred at −40° C. for 3 h. Then, ethyl acetate(30 ml) was added, and the mixture was stirred for further 20 min at−40° C. followed by dropwise addition of aqueous tartaric acid (1 M, 30ml). The mixture was allowed to warm to 0° C. and filtered at thistemperature. The filtrate was extracted with ethyl acetate severaltimes, and the combined organic phases were subsequently washed withsaturated aqueous sodium hydrogencarbonate and with brine, dried oversodium sulfate, filtered and concentrated under reduced pressure. Thecrude product thus obtained (2.60 g, 53% of th.) was used in the nextstep without further purification.

LC-MS (method 4): R_(t)=0.59 min; MS (ESIpos): m/z=165 (M+H)⁺.

Example 20A(2E)-2-[(6-Fluoro-1H-indazol-5-yl)methylidene]-3-oxobutanenitrile

The title compound was prepared from 3.7 g (80% purity, 18.0 mmol)6-fluoro-1H-indazole-5-carbaldehyde (Example 19A) and 2.08 g (19.84mmol) sodium (1Z)-1-cyanoprop-1-en-2-olate in analogy to the proceduredescribed in Example 2A yielding 2.5 g (61% of th.) of product which wasused in subsequent steps without further purification.

LC-MS (method 2): R_(t)=0.71 min; MS (ESIpos): m/z=230 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=13.90 (s, 1H), 8.59 (s, 1H), 8.46 (s, 1H),8.23 (d, 1H), 7.80 (d, 1H), 2.5 (br. s, 31-1) ppm.

Example 21A 3-Amino-3-[4-(trifluoromethyl)phenyl]prop-2-enenitrile

The title compound was prepared following the procedure described forExample 11A using 4-(trifluoromethyl)benzonitrile (500 mg, 2.89 mmol) toyield 606 mg (99% of th.) of the crude product which was used in thenext step without further purification.

LC-MS (method 5): R_(t)=2.08 min; MS (EIpos): m/z=213 (M+H)⁺.

PREPARATION EXAMPLES Example 12-Methyl-4-(3-methyl-1H-indazol-5-yl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carbonitrile

Method A:

A solution of 300 mg (1.332 mmol)(2E)-2-[(3-methyl-1H-indazol-5-yl)methylidene]-3-oxobutane-nitrile(Example 2A), 136 mg (1.332 mmol) furan-2,4(3H,5H)-dione and 123 mg(1.598 mmol) ammonium acetate in acetic acid (6.3 ml) was stirred at110° C. for 3 h. The reaction mixture was then concentrated underreduced pressure, and the residue was purified by flash chromatography(silica gel; dichloromethane/methanol gradient, final mixture 30:1 v/v)to give 59 mg (14% of th.) of the racemic title compound.

Method B:

A solution of 100 mg (0.624 mmol) 3-methyl-1H-indazole-5-carbaldehyde(Example 1A), 54 mg (0.624 mmol) 3-aminobut-2-enenitrile and 120 mg(0.624 mmol) ethyl 4-(acetoxy)-3-oxobutanoate [preparation: U.S. Pat.No. 4,720,572 (Example 1)] in 1-propanol (2 ml) was stirred at refluxtemperature overnight. Then, concentrated hydrochloric acid (115 μl) andwater (350 μl) were added, and stirring was continued at 100° C. for 1h. After cooling, the mixture was directly purified by preparativeRP-HPLC (acetonitrile/water+0.1% TFA gradient) to yield 103 mg (51% ofth.) of the racemic title compound.

LC-MS (method 2): R_(t)=0.72 min; MS (ESIpos): m/z=307 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=12.62 (br. s, 1H), 10.69 (br. s, 1H), 7.50(s, 1H), 7.42 (d, 1H), 7.23 (d, 1H), 4.89 (dd, 2H), 4.61 (s, 1H), 2.48(s, 3H), 2.12 (s, 3H) ppm.

Example 2 and Example 32-Methyl-4-(3-methyl-1H-indazol-5-yl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carbonitrile(Enantiomer 1 and 2)

The racemic compound from Example 1 (125 mg) was separated into theenantiomers by HPLC chromatography on a chiral phase [column: DaicelChiralpak AS-H, 5 μm, 250 mm×20 mm; eluent: iso-hexane/ethanol 65:35v/v; flow rate: 15 ml/min; temperature: 35° C.; UV detection: 220 nm]:

Example 2 Enantiomer 1

Yield: 49 mg (chemical purity >99%, >99% ee)

R_(t)=5.66 min [column: Daicel Chiralpak AS-H, 5 μm, 250 mm×4.6 mm;Eluent: iso-hexane/ethanol

70:30+0.2% diethylamine; flow rate: 1 ml/min; temperature: 30° C.; UVdetection: 235 nm].

Example 3 Enantiomer 2

Yield: 45 mg (chemical purity >95%, >99% ee)

R_(t)=10.10 min [column: Daicel Chiralpak AS-H, 5 μm, 250 mm×4.6 mm;Eluent: iso-hexane/ethanol 70:30+0.2% diethylamine; flow rate: 1 ml/min;temperature: 30° C.; UV detection: 235 nm].

Example 44-(3-Ethyl-1H-indazol-5-yl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carbonitrile

The title compound was prepared from 600 mg (2.508 mmol)(2E)-2-[(3-ethyl-1H-indazol-5-yl)-methylidene]-3-oxobutanenitrile(Example 7A), 256 mg (2.508 mmol) furan-2,4(3H,5H)-dione and 232 mg(3.010 mmol) ammonium acetate in analogy to the procedure described inExample 1 yielding 98 mg (12% of th.) of the racemic compound afterpurification by flash chromatography (silica gel;dichloromethane/methanol gradient, final mixture 30:1 v/v).

LC-MS (method 2): R_(t)=0.81 min; MS (ESIpos): m/z=321 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=12.61 (br. s, 1H), 10.66 (br. s, 1H), 7.54(s, 1H), 7.42 (d, 1H), 7.22 (d, 1H), 4.89 (dd, 2H), 4.62 (s, 1H), 2.90(q, 2H), 2.12 (s, 3H), 1.31 (t, 3H) ppm.

Example 5 and Example 64-(3-Ethyl-1H-indazol-5-yl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carbonitrile(Enantiomer 1 and 2)

The racemic compound from Example 4 (90 mg) was separated into theenantiomers by HPLC chromatography on a chiral phase [column: DaicelChiralpak AS-H, 5 μm, 250 mm×20 mm; eluent: iso-hexane/ethanol 50:50v/v; flow rate: 15 ml/min; temperature: 30° C.; UV detection: 220 nm]:

Example 5 Enantiomer 1

Yield: 25 mg (chemical purity >98.5%, >99% ee)

R_(t)=3.90 min [column: Daicel Chiralpak AS-H, 5 μm, 250 mm×4.6 mm;eluent: iso-hexane/ethanol 50:50; flow rate: 1 ml/min; temperature: 30°C.; UV detection: 220 nm].

Example 6 Enantiomer 2

Yield: 25 mg (chemical purity >94%, >98.8% ee)

R_(t)=6.24 min [column: Daicel Chiralpak AS-H, 5 μm 250 mm×4.6 mm;eluent: iso-hexane/ethanol 50:50; flow rate: 1 ml/min; temperature: 30°C.; UV detection: 220 nm].

Example 72,8,8-Trimethyl-4-(3-methyl-1H-indazol-5-yl)-5-oxo-1,5,7,8-tetrahydro-4H-pyrano[4,3-b]pyridine-3-carbonitrile

The title compound was prepared from 200 mg (0.888 mmol)(2E)-2-(3-methyl-1H-indazol-5-yl)-methylidene]-3-oxobutanenitrile(Example 2A), 126 mg (0.888 mmol)5,5-dimethyldihydro-2H-pyran-2,4(31)dione [preparation: US2006/0014826-A1 (Intermediate 6)] and 102 mg (1.332 mmol) ammoniumacetate in analogy to the procedure described in Example 1 yielding 51mg (16% of th.) after purification by preparative RP-HPLC(acetonitrile/water+0.1% TFA gradient) followed by flash chromatography(silica gel; ethyl acetate/cyclohexane gradient, final mixture 5:1 v/v).

LC-MS (method 4): R_(t)=0.76 min; MS (ESIpos): m/z=349 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=12.60 (s, 1H), 8.94 (s, 1H), 7.43-7.38 (m,2H), 7.29 (d, 1H), 4.56 (s, 1H), 3.90 (dd, 2H), 2.48 (s, 3H), 2.14 (s,3H), 1.25 (s, 6H) ppm.

Example 82-Methyl-4-(3-methyl-1H-indazol-5-yl)-5-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,4-b]pyridine-3-carbonitrile

A solution of 200 mg (0.888 mmol)(2E)-2-(3-methyl-1H-indazol-5-yl)methylidene]-3-oxobutane-nitrile(Example 2A), 353 mg (0.888 mmol, approx. 50% purity) tert-butyl4-hydroxy-2-oxo-2,5-dihydro-1H-pyrrole-1-carboxylate [W.-R. Li et al.,J. Org. Chem. 2002, 67, 4702-4706] and 102 mg (1.332 mmol) ammoniumacetate in acetic acid (4 ml) was stirred at 100° C. for 45 min. Thereaction mixture was concentrated under reduced pressure, and theresidue was purified first by flash chromatography (silica gel;dichloromethane/methanol gradient, final mixture 10:1 v/v) and then bypreparative RP-HPLC (acetonitrile/water+0.1% TFA gradient) to give 31 mg(11% of th.) of the title compound.

LC-MS (method 2): R_(t)=0.63 min; MS (ESIpos): m/z=306 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=12.58 (br. s, 1H), 9.72 (s, 1H), 7.44 (s,1H), 7.40 (d, 1H), 7.21 (d, 1H), 4.53 (s, 1H), 3.91 (dd, 2H), 2.48 (s,3H), 2.10 (s, 3H) ppm.

Example 92,7,7-Trimethyl-4-(3-methyl-1H-indazol-5-yl)-5-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,4-b]pyridine-3-carbonitrile

A solution of 200 mg (0.888 mmol)(2E)-2-[(3-methyl-1H-indazol-5-yl)methylidene]-3-oxobutane-nitrile(Example 2A), 226 mg (0.888 mmol, approx. 50% purity)4-hydroxy-5,5-dimethyl-1,5-dihydro-2H-pyrrol-2-one [K. Matsuo et al.,Chem. Pharm. Bull. 1984, 32, 3724-3729] and 102 mg (1.332 mmol) ammoniumacetate in acetic acid (4 ml) was stirred at 100° C. for 15 min. Thereaction mixture was concentrated under reduced pressure, and theresidue was purified first by preparative RP-HPLC(acetonitrile/water+0.1% TFA gradient) and then by preparative TLC(eluent: dichloromethane/methanol 10:1) to give 33 mg (11% of th.) ofthe title compound.

LC-MS (method 4): R_(t)=0.65 min; MS (ESIpos): m/z=334 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=12.58 (s, 1H), 9.58 (s, 1H), 7.61 (s, 1H),7.41-7.38 (m, 2H), 7.18 (d, 1H), 4.49 (s, 1H), 2.48 (s, 3H), 2.12 (s,3H), 1.35 (s, 3H), 1.33 (s, 3H) ppm.

Example 107-(1H-Indazol-5-yl)-5-methyl-2,3,4,7-tetrahydrothieno[3,2-b]pyridine-6-carbonitrile-1,1-dioxide

127 mg (0.947 mmol) dihydrothiophen-3(2H)-one-1,1-dioxide, 266 mg (0.947mmol) (2E)-2-(1H-indazol-5-ylmethylidene)-3-oxobutanenitrile (Example8A) and 88 mg (1.136 mmol) ammonium acetate in acetic acid (5 ml) wereheated to reflux overnight. After cooling, the mixture was evaporated todryness, and the residue was purified by preparative RP-HPLC(acetonitrile/water gradient) to yield 16 mg (5% of th.) of the titlecompound.

LC-MS (method 5): R_(t)=1.31 min; MS (ESIpos): m/z=327 (M+H)⁺¹H-NMR (400MHz, DMSO-d₆): δ=9.75 (s, 1H), 8.05 (s, 1H), 7.59 (s, 1H), 7.49 (d, 1H),7.26 (d, 1H), 4.73 (s, 1H), 3.37-3.26 (m, 2H), 3.01-2.93 (m, 1H),2.84-2.77 (m, 1H), 2.07 (s, 3H) ppm.

Example 115-Methyl-7-(3-methyl-1H-indazol-5-yl)-2,3,4,7-tetrahydrothieno[3,2-b]pyridine-6-carbonitrile-1,1-dioxide

850 mg (6.336 mmol) dihydrothiophen-3(2H)-one-1,1-dioxide, 1.78 g (6.336mmol) (2E)-2-[(3-methyl-1H-indazol-5-yl)methylidene]-3-oxobutanenitrile(Example 2A) and 586 mg (7.603 mmol) ammonium acetate in acetic acid (30ml) were heated to reflux overnight. After cooling, the mixture wasevaporated to dryness, and the residue was taken up in ethyl acetate andwashed with water and brine. The organic layer was separated and driedover sodium sulfate. After filtration and evaporation to dryness, theremaining solid was purified by preparative RP-HPLC (acetonitrile/watergradient) to yield 89 mg (4% of th.) of the title compound.

LC-MS (method 5): R_(t)=1.36 min; MS (ESIpos): m/z=341 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=9.73 (s, 1H), 7.50 (s, 1H), 7.41 (d, 1H),7.24 (d, 1H), 4.73 (s, 1H), 3.37-3.26 (m, 2H), 3.01-2.93 (m, 1H),2.84-2.77 (m, 1H), 2.47 (s, 3H), 2.07 (s, 3H) ppm.

Example 122-Methyl-4-(3-methyl-1H-indazol-5-yl)-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carbonitrile

273 mg (2.442 mmol) cyclohexane-1,3-dione, 500 mg (2.222 mmol)(2E)-2-[(3-methyl-1H-indazol-5-yl)methylidene]-3-oxobutanenitrile(Example 2A) and 205 mg (2.664 mmol) ammonium acetate in acetic acid (5ml) were heated to 50° C. overnight. Then, additional ammonium acetate(102 mg, 1.332 mmol) was added, and the mixture was heated to reflux for24 h. After cooling, the mixture was evaporated to dryness, and theresidue was taken up in ethyl acetate and washed with water twice. Thecombined aqueous phases were extracted with ethyl acetate. The organiclayers were combined and dried over sodium sulfate. After filtration andevaporation to dryness, the remaining solid was purified by preparativeRP-HPLC (acetonitrile/water gradient) to yield 55 mg (8% of th.) of thetitle compound.

LC-MS (method 5): R_(t)=1.42 min; MS (ESIpos): m/z=319 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=12.52 (s, 1H), 9.48 (s, 1H), 7.38 (s, 1H),7.36 (d, 1H), 7.17 (d, 1H), 4.54 (s, 1H), 2.51 (m, 2H), 2.45 (s, 3H),2.27-2.12 (m, 2H), 2.07 (s, 3H), 1.94-1.89 (m, 1H), 1.85-1.74 (m, 1H)ppm.

Example 132-Methyl-4-(3-methyl-1H-indazol-5-yl)-5-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carbonitrile

91 mg (0.936 mmol) cyclopentane-1,3-dione, 150 mg (0.936 mmol)3-methyl-1H-indazole-5-carbaldehyde (Example 1A) and piperidine (0.1 ml)in ethanol (8 ml) were heated to reflux for 1.5 h and then left standingwithout stirring at room temperature overnight. The mixture was thenevaporated to dryness, the remaining solid was dissolved in acetic acid(8 ml), and 77 mg (0.936 mmol) 3-aminobut-2-enenitrile were added. Thesolution was heated to reflux for 2 h. After cooling, the mixture wasevaporated to dryness again, and the remaining solid was purified bypreparative RP-HPLC (acetonitrile/water gradient) to yield 34 mg (12% ofth.) of the title compound.

LC-MS (method 5): R_(t)=1.32 min; MS (ESIpos): m/z=305 (M+H)⁺

¹-NMR (400 MHz, DMSO-d₆): δ=12.55 (s, 1H), 10.06 (s, 1H), 7.43 (br. s,1H), 7.37 (d, 1H), 7.17 (dd, 1H), 4.49 (s, 1H), 2.64-2.58 (m, 2H), 2.46(s, 3H), 2.26-2.23 (m, 2H), 2.12 (s, 3H) ppm.

Example 144-(1H-Indazol-5-yl)-2-methyl-5-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carbonitrile

100 mg (1.026 mmol) cyclopentane-1,3-dione, 150 mg (1.026 mmol)1H-indazole-5-carbaldehyde and piperidine (0.1 ml) in ethanol (8 ml)were heated to reflux for 4 h. The mixture was then evaporated todryness, the remaining solid was dissolved in acetic acid (8 ml), and 84mg (1.026 mmol) 3-aminobut-2-enenitrile were added. The solution washeated to reflux for 2 h. After cooling, the mixture was evaporated todryness again, and the remaining solid was purified by preparativeRP-HPLC (acetonitrile/water gradient) to yield 40 mg (13% of th.) of thetitle compound.

LC-MS (method 5): R_(t)=1.27 min; MS (ESIpos): m/z=291 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=12.99 (s, 1H), 10.08 (s, 1H), 8.02 (s, 1H),7.52 (s, 1H), 7.46 (d, 1H), 7.22 (dd, 1H), 4.49 (s, 1H), 2.69-2.56 (m,2H), 2.26-2.23 (m, 2H), 2.12 (s, 3H) ppm.

Example 158-(3-Methyl-1H-indazol-5-yl)-3,4,7,8-tetrahydro-1H,5H-difuro[3,4-b:3′,4′-e]pyridine-1,5-dione

A solution of 120 mg (0.75 mmol) 3-methyl-1H-indazole-5-carbaldehyde(Example 1A) and 75 mg (0.75 mmol) furan-2,4(3H,5H)-dione in 1-pentanol(1.5 ml) was stirred at reflux for 1 h. The mixture was then cooled toroom temperature, water (1.5 ml) was added, and the mixture wasconcentrated under reduced pressure. The residue was dissolved in aceticacid (1.5 ml), and 111 mg (1.12 mmol) 3-aminofuran-2(511)-one [U. Kraatzet al., Chem. Ber. 1971, 104, 2458-2466] were added. The resultingsolution was stirred at 100° C. for 2 h, then cooled to room temperatureand concentrated under reduced pressure. The residue was purified bypreparative RP-HPLC (acetonitrile/water gradient) to give 68 mg (27% ofth.) of the title compound.

LC-MS (method 4): R_(t)=0.60 min; MS (ESIpos): m/z=324 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=12.60 (s, 1H), 10.21 (s, 1H), 7.53 (s, 1H),7.41 (d, 1H), 7.24 (d, 1H), 4.97-4.81 (m, 4H), 4.45-4.35 (m, 1H), 2.47(s, 3H) ppm.

Example 164-(3-Methyl-1H-indazol-5-yl)-5-oxo-2-(trifluoromethyl)-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carbonitrile

100 mg (0.624 mmol) 3-methyl-1H-indazole-5-carbaldehyde (Example 1A) and62.5 mg (0.624 mmol) furan-2,4(3H,5H)-dione were heated up to reflux in1-pentanol (3 ml) for 1 h. After addition of 425 mg (3.120 mmol)3-amino-4,4,4-trifluorobut-2-enenitrile [A. W. Lutz, U.S. Pat. No.3,635,977], the reaction mixture was stirred at 100° C. for further 4 h.Then, conc. hydrochloric acid (115 μl) and water (350 μl) were added,and the mixture was stirred at 100° C. for another 1 h. After cooling,the mixture was directly purified by RP-HPLC (acetonitrile/water+0.1%TFA gradient) to give 33 mg (14% of th.) of the title compound.

LC-MS (method 4): R_(t)=0.78 min; MS (ESIpos): m/z=361 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=12.70 (br. s, 1H), 11.04 (s, 1H), 7.60 (s,1H), 7.29 (d, 1H), 4.95 (dd, 2H), 4.90 (s, 1H), 2.50 (s, 3H) ppm.

Example 171,2-Dimethyl-4-(3-methyl-1H-indazol-5-yl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carbonitrile

A solution of 100 mg (0.326 mmol)2-methyl-4-(3-methyl-1H-indazol-5-yl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carbonitrile(Example 1) in DMF (2 ml) was cooled to 0° C. 128 mg (0.392 mmol)caesium carbonate were added at this temperature, and after 30 min 14 μl(0.229 mmol) methyl iodide were added dropwise. After stirring overnightat rt, additional methyl iodide (2 μl) was added, and stirring at rt wascontinued for further 3 h. Again, methyl iodide (6 μl) and a smallamount of caesium carbonate were added, and the reaction mixture wasstirred at rt over-night before water (1 ml) was added. The solution wasdirectly purified first by preparative RP-HPLC (acetonitrile/water+0.1%TFA gradient) followed by preparative TLC (eluent:dichloromethane/ethanol 20:1) to give 11 mg (11% of th.) of the titlecompound.

LC-MS (method 2): R_(t)=0.75 min; MS (ESIpos): m/z=321 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=12.62 (br. s, 1H), 7.51 (s, 1H), 7.42 (d,1H), 7.26 (d, 1H), 5.07 (dd, 2H), 4.61 (s, 1H), 3.18 (s, 3H), 2.48 (s,3H), 2.28 (s, 3H) ppm.

Example 184-(3-Methyl-1H-indazol-5-yl)-3-oxo-1,3,4,6,8,9-hexahydrofuro[3′,4′:5,6]pyrido[2,1-c][1,4]oxazine-5-carbonitrile

In flask A, 235 mg (1.469 mmol) 3-methyl-1H-indazole-5-carbaldehyde(Example 1A) and 150 mg (1.469 mmol) furan-2,4(3H,5H)-dione were heatedup to reflux in 1-pentanol (3 ml) for 1 h and then cooled to roomtemperature. In a second flask B, a mixture of 494 mg (2.203 mmol)tert-butyl (2E/Z)-cyano(morpholin-3-ylidene)ethanoate (Example 10A) in 6M hydrochloric acid (21 ml) was heated to 100° C. for 15 min. Aftercooling to room temperature, the solution in flask B was concentratedunder reduced pressure, and the remaining solid was dissolved in aceticacid (4 ml). This solution was added to flask A, and the resultingmixture was stirred at 100° C. for 1.5 h. The mixture was then cooled toroom temperature and concentrated under reduced pressure. The residuewas purified by flash chromatography (silica gel; toluene/ethanolgradient, final mixture 10:1 v/v) to yield the title compound as a whitesolid (151 mg, 29% of th.).

LC-MS (method 4): R_(t)=0.70 min; MS (ESIpos): m/z=349 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=12.63 (br. s, 1H), 7.55 (s, 1H), 7.44 (d,1H), 7.30 (d, 1H), 5.09 (s, 2H), 4.69 (s, 1H), 4.59 (m, 2H), 3.99 (m,2H), 3.55 (m, 1H), 3.44 (m, 1H), 2.54 (s, 3H) ppm.

Example 192-(5-Methoxypyridin-2-yl)-4-(3-methyl-1H-indazol-5-yl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]-pyridine-3-carbonitrile

A solution of 172 mg (1.073 mmol) 3-methyl-1H-indazole-5-carbaldehyde(Example 1A), 188 mg (1.073 mmol) crude3-amino-3-(6-methoxypyridin-3-yl)prop-2-enenitrile (Example 11A) and 242mg (1.288 mmol) ethyl 4-(acetyloxy)-3-oxobutanoate [Tetrahedron 1978,34, 1453-5] in 1-propanol (4 ml) was heated up to reflux for 12 h andthen cooled to room temperature. Hydrochloric acid (3 M, 0.75 ml) wasadded, and the resulting mixture was again heated to 100° C. for 1 h.After cooling to room temperature, the solution was concentrated underreduced pressure, and the remaining solid was purified by preparativeRP-HPLC (acetonitrile/water gradient) followed by flash chromatography(silica gel; dichloromethane/methanol gradient, final mixture 95:5 v/v)to yield the title compound as a white solid (30.7 mg, 7% of th.).

LC-MS (method 4): R_(t)=0.77 min; MS (ESIpos): m/z=400 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=12.64 (s, 1H), 10.43 (br. s, 1H), 8.43 (d,1H), 7.92 (m, 1H), 7.60 (s, 1H), 7.46 (m, 1H), 7.36 (m, 1H), 7.01 (d,1H), 5.00-4.83 (m, 2H), 4.79 (s, 1H), 3.91 (s, 3H), 2.54 (s, 3H) ppm.

Example 202-(2-Methoxyethyl)-4-(3-methyl-1H-indazol-5-yl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carbonitrile

A solution of 100 mg (0.624 mmol) 3-methyl-1H-indazole-5-carbaldehyde(Example 1A), 87 mg (0.69 mmol) crude 5-methoxy-3-oxopentanenitrile(Example 12A), 120 mg (0.624 mmol) ethyl 4-(acetyloxy)-3-oxobutanoate[Tetrahedron 1978, 34, 1453-5] and 147 mg (1.87 mmol) ammonium acetatein 1-propanol (2 ml) was heated up to reflux for 12 h and then cooled toroom temperature. Hydrochloric acid (3 M, 0.465 ml) was added, and theresulting mixture was again heated to 100° C. for 1 h. After cooling toroom temperature, the solution was concentrated under reduced pressure,and the remaining solid was purified by preparative RP-HPLC(acetonitrile/water gradient, final mixture 9:1 v/v) to yield the titlecompound as a white solid (51.2 mg, 23% of th.).

LC-MS (method 4): R₁=0.69 min; MS (ESIpos): m/z=351 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=12.62 (s, 1H), 10.12 (s, 1H), 7.52 (s, 1H),7.42 (m, 1H), 7.25 (m, 1H), 4.95-4.80 (m, 2H), 4.62 (s, 1H), 3.61 (t,2H), 3.30 (s, 3H), 2.78-2.55 (m, 2H), 2.47 (s, 3H) ppm.

Example 214-[3-(2,3-Dihydro-1,4-benzodioxin-6-yl)-1H-indazol-5-yl]-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro-[3,4-b]pyridine-3-carbonitrile

To a degassed solution of 120 mg (0.323 mmol)4-(3-bromo-1H-indazol-5-yl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carbonitrile(Example 24) and 69.8 mg (0.388 mmol)2,3-dihydro-1,4-benzodioxin-6-ylboronic acid in anhydrous 1,4-dioxane(4.5 ml) were added under inert gas atmosphere 37.4 mg (0.032 mmol)tetrakis(triphenylphosphine)palladium(0) and aqueous sodium bicarbonatesolution (2 M, 0.77 ml). The resulting mixture was stirred at 95° C. for12 h. After cooling to room temperature and concentration under reducedpressure, the remaining solid was dissolved in ethyl acetate (20 ml).The solution was subsequently washed with water and brine, dried oversodium sulfate and concentrated under reduced pressure. The crudeproduct was purified by preparative RP-HPLC (acetonitrile/watergradient, final mixture 95:5 v/v) to yield the title compound as a whitesolid (26 mg, 19% of th.).

LC-MS (method 4): R_(t)=0.82 min; MS (ESIpos): m/z=427 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=13.12 (s, 1H), 10.18 (br. s, 1H), 7.83 (s,1H), 7.54 (d, 1H), 7.45-7.38 (m, 2H), 7.29 (m, 1H), 7.02 (d, 1H),4.97-4.80 (m, 2H), 4.73 (s, 1H), 4.31 (s, 4H), 2.13 (s, 3H) ppm.

Example 222-Methyl-5-oxo-4-{3-[6-(propan-2-yloxy)pyridin-3-yl}-1H-indazol-5-yl]-1,4,5,7-tetrahydrofuro-[3,4-b]pyridine-3-carbonitrile

To a degassed solution of 120 mg (0.323 mmol)4-(3-bromo-1H-indazol-5-yl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carbonitrile(Example 24) and 70.2 mg (0.388 mmol)[6-(propan-2-yloxy)pyridin-3-yl]boronic acid in anhydrous 1,4-dioxane(3.5 ml) were added under inert gas atmosphere 37.4 mg (0.032 mmol)tetrakis(triphenylphosphine)palladium(0) and aqueous sodium bicarbonatesolution (2 M, 0.77 ml). The resulting mixture was stirred at 100° C.for 12 h. After cooling to room temperature and concentration underreduced pressure, the remaining solid was dissolved in ethyl acetate (20ml). The solution was subsequently washed with water and brine, driedover sodium sulfate and concentrated under reduced pressure. The crudeproduct was purified by preparative RP-HPLC (acetonitrile/watergradient, final mixture 95:5 v/v) to yield the title compound as a whitesolid (27 mg, 19% of th.).

LC-MS (method 4): R_(t)=0.90 min; MS (ESIpos): m/z=428 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=13.25 (s, 1H), 10.17 (s, 1H), 8.73 (d, 1H),8.22 (dd, 1H), 7.91 (s, 1H), 7.58 (s, 1H), 7.32 (d, 1H), 6.92 (d, 1H),5.34 (sept, 1H), 4.97-4.80 (m, 2H), 4.75 (s, 1H), 2.13 (s, 3H), 1.35 (d,6H) ppm.

Example 234-(3-Methyl-1H-indazol-5-yl)-3-oxo-1,4,6,7,8,9-hexahydro-3H-furo[3,4-c]quinolizine-5-carbonitrile

A solution of 138 mg (0.86 mmol) 3-methyl-1H-indazole-5-carbaldehyde(Example 1A), 105 mg (1.073 mmol) piperidin-2-ylidene-ethanenitrile [WO2008/071451, Synth. Prep. 5] and 194 mg (1.031 mmol) ethyl4-(acetyloxy)-3-oxobutanoate [Tetrahedron 1978, 34, 1453-5] in1-propanol (3 ml) was heated up to reflux for 12 h and then cooled toroom temperature. Hydrochloric acid (3 M, 0.60 ml) was added, and theresulting mixture was again heated to 100° C. for 1 h. After cooling toroom temperature, the solution was concentrated under reduced pressure,and the remaining solid was purified by preparative TLC (silica gel;eluent: dichloromethane/ethanol 20:1 v/v). The product was furtherpurified by trituration in a mixture of acetonitrile/methanol/water(2:6:1 v/v/v). The precipitate was collected by filtration and dried invacuo to yield the title compound as a white solid (18 mg, 6% of th.).

LC-MS (method 4): R_(t)=0.78 min; MS (ESIpos): m/z=347 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=12.62 (s, 1H), 7.52 (s, 1H), 7.43 (d, 1H),7.27 (d, 1H), 5.12-4.98 (m, 2H), 4.63 (s, 1H), 3.60-3.39 (m, 2H),2.75-2.60 (m, 2H), 2.54 (s, 3H), 1.90-1.80 (m, 2H), 1.78-1.62 (m, 2H)ppm.

Example 244-(3-Bromo-1H-indazol-5-yl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carbonitrile

A solution of 2.45 g (10.89 mmol) 3-bromo-1H-indazole-5-carbaldehyde(Example 13A), 0.931 g (10.89 mmol) 3-aminobut-2-enenitrile and 2.09 g(10.89 mmol) ethyl 4-(acetyloxy)-3-oxobutanoate [Tetrahedron 1978, 34,1453-5] in 1-propanol (50 ml) was heated up to reflux for 12 h and thencooled to room temperature. Hydrochloric acid (3 M, 14 ml) was added,and the resulting mixture was again heated to 100° C. for 1 h. Aftercooling to room temperature, the solution was concentrated under reducedpressure, and the remaining solid was purified by preparative RP-HPLC(acetonitrile/water gradient, final mixture 95:5 v/v) to yield the titlecompound as a pale yellow solid (756 mg, 19% of th.).

LC-MS (method 5): R_(t)=1.52 min; MS (ESIpos): m/z=371 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=13.44 (s, 1H), 10.21 (s, 1H), 7.57 (m, 1H),7.41-7.37 (m, 2H), 5.00-4.82 (m, 2H), 4.72 (s, 1H), 2.13 (s, 3H) ppm.

Example 252-(4-Fluorophenyl)-4-(3-methyl-1H-indazol-5-yl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carbonitrile

A solution of 241 mg (L51 mmol) 3-methyl-1H-indazole-5-carbaldehyde(Example 1A), 244 mg (1.51 mmol)3-amino-3-(4-fluorophenyl)prop-2-enenitrile [J. Heterocyclic Chem. 1998,35, 805-810] and 340 mg (1.81 mmol) ethyl 4-(acetyloxy)-3-oxobutanoate[Tetrahedron 1978, 34, 1453-5] in 1-propanol (4 ml) was heated up toreflux for 12 h and then cooled to room temperature. Hydrochloric acid(3 M, 1.05 ml) was added, and the resulting mixture was again heated to100° C. for 1 h. After cooling to room temperature, the solution wasconcentrated under reduced pressure, and the remaining solid waspurified by preparative RP-HPLC (acetonitrile/water gradient, finalmixture 95:5 v/v) to yield the title compound as a white solid (200 mg,34% of th.).

LC-MS (method 4): R_(t)=0.83 min; MS (ESIpos): m/z=387 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=12.64 (s, 1H), 10.39 (s, 1H), 7.70-7.63 (m,2H), 7.60 (s, 1H), 7.46 (d, 1H), 7.43-7.33 (m, 3H), 5.00-4.84 (m, 2H),4.78 (s, 1H), 2.54 (s, 3H) ppm.

Example 26 and Example 272-(4-Fluorophenyl)-4-(3-methyl-1H-indazol-5-yl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carbonitrile(Enantiomer 1 and 2)

The racemic compound from Example 25 (100 mg) was separated into theenantiomers by HPLC chromatography on a chiral phase [column: DaicelChiralpak AS-H, 5 gm, 250 mm×20 mm; eluent: iso-hexane/ethanol 50:50v/v; flow rate: 15 ml/min; temperature: 30° C.; UV detection: 220 nm]:

Example 26 Enantiomer 1

Yield: 38 mg (chemical purity >98.5%, >99.5% ee)

R_(t)=4.06 min [column: Daicel Chiralpak AS-H, 5 μm, 250 mm×4.6 mm;eluent: iso-hexane/ethanol 50:50; flow rate: 1 ml/min; temperature: 40°C.; UV detection: 220 nm].

Example 27 Enantiomer 2

Yield: 51 mg (chemical purity >99.5%, >99.5% ee)

R_(t)=8.43 min [column: Daicel Chiralpak AS-H, 5 μm, 250 mm×4.6 mm;eluent: iso-hexane/ethanol 50:50; flow rate: 1 ml/min; temperature: 40°C.; UV detection: 220 nm].

Example 282-(4-Chlorophenyl)-4-(3-methyl-1H-indazol-5-yl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carbonitrile

A solution of 245 mg (1.53 mmol) 3-methyl-1H-indazole-5-carbaldehyde(Example 1A), 300 mg (1.68 mmol)3-amino-3-(4-chlorophenyl)prop-2-enenitrile [J. Heterocyclic Chem. 1998,35, 805-810] and 287 mg (1.53 mmol) ethyl 4-(acetyloxy)-3-oxobutanoate[Tetrahedron 1978, 34, 1453-5] in 1-propanol (6 ml) was heated up toreflux for 12 h and then cooled to room temperature. Hydrochloric acid(3 M, 1.2 ml) was added, and the resulting mixture was again heated to100° C. for 1 h. After cooling to room temperature, the solution wasconcentrated under reduced pressure, and the remaining solid waspurified by preparative RP-HPLC (acetonitrile/water gradient, finalmixture 95:5 v/v) to yield the title compound as a pale yellow solid(248 mg, 40% of th.).

LC-MS (method 4): R_(t)=0.88 min; MS (ESIpos): m/z=403 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ=12.64 (s, 1H), 10.41 (s, 1H), 7.63 (m, 4H),7.60 (s, 1H), 7.46 (d, 1H), 7.35 (m, 1H), 5.00-4.84 (m, 2H), 4.79 (s,1H), 2.54 (s, 3H) ppm.

Example 292-(4-Chloro-3-fluorophenyl)-4-(3-methyl-1H-indazol-5-yl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]-pyridine-3-carbonitrile

A solution of 148 mg (0.93 mmol) 3-methyl-1H-indazole-5-carbaldehyde(Example 1A), 200 mg (1.02 mmol)3-amino-3-(4-chloro-3-fluorophenyl)prop-2-enenitrile (Example 14A) and174 mg (0.93 mmol) ethyl 4-(acetyloxy)-3-oxobutanoate [Tetrahedron 1978,34, 1453-5] in 1-propanol (3.5 ml) was heated up to reflux for 12 h andthen cooled to room temperature. Hydrochloric acid (3 M, 0.76 ml) wasadded, and the resulting mixture was again heated to 100° C. for 1 h.After cooling to room temperature, the solution was concentrated underreduced pressure, and the remaining solid was purified by preparativeRP-HPLC (acetonitrile/water gradient, final mixture 95:5 v/v) followedby preparative TLC (silica gel; eluent: dichloromethane/methanol 20:1v/v) to yield the title compound as a white solid (50 mg, 13% of th.).

LC-MS (method 2): R_(t)=1.02 min; MS (ESIpos): m/z=421 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=12.63 (s, 1H), 10.46 (s, 1H), 7.80 (m, 1H),7.73 (m, 1H), 7.60 (s, 1H), 7.52-7.44 (m, 2H), 7.36 (m, 1H), 5.00-4.84(m, 2H), 4.79 (s, 1H), 2.54 (s, 3H) ppm.

Example 302-(3,5-Difluorophenyl)-4-(3-methyl-1H-indazol-5-yl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carbonitrile

A solution of 162 mg (1.01 mmol) 3-methyl-1H-indazole-5-carbaldehyde(Example 1A), 200 mg (1.11 mmol)3-amino-3-(3,5-difluorophenyl)prop-2-enenitrile (Example 15A) and 190 mg(1.01 mmol) ethyl 4-(acetyloxy)-3-oxobutanoate [Tetrahedron 1978, 34,1453-5] in 1-propanol (4 ml) was heated up to reflux for 12 h and thencooled to room temperature. Hydrochloric acid (3 M, 0.80 ml) was added,and the resulting mixture was again heated to 100° C. for 1 h. Aftercooling to room temperature, the solution was concentrated under reducedpressure, and the remaining solid was purified by preparative RP-HPLC(acetonitrile/water gradient, final mixture 95:5 v/v) to yield the titlecompound as a pale yellow solid (39 mg, 10% of th.).

LC-MS (method 4): R_(t)=0.86 min; MS (ESIpos): m/z=405 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=12.63 (s, 1H), 10.48 (s, 1H), 7.60 (s, 1H),7.52-7.32 (m, 5H), 5.00-4.84 (m, 2H), 4.79 (s, 1H), 2.54 (s, 3H) ppm.

Example 312-(2,4-Difluorophenyl)-4-(3-methyl-1H-indazol-5-yl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carbonitrile

A solution of 232 mg (1.45 mmol) 3-methyl-1H-indazole-5-carbaldehyde(Example 1A), 287 mg (1.59 mmol)3-amino-3-(2,4-difluorophenyl)prop-2-enenitrile (Example 16A) and 273 mg(1.45 mmol) ethyl 4-(acetyloxy)-3-oxobutanoate [Tetrahedron 1978, 34,1453-5] in 1-propanol (6 ml) was heated up to reflux for 12 h and thencooled to room temperature. Hydrochloric acid (3 M, 0.80 ml) was added,and the resulting mixture was again heated to 100° C. for 1 h. Aftercooling to room temperature, the solution was concentrated under reducedpressure, and the remaining solid was purified by preparative RP-HPLC(acetonitrile/water gradient, final mixture 95:5 v/v) followed by flashchromatography (silica gel; dichloromethane/methanol gradient, finalmixture 95:5 v/v) to yield the title compound as a pale yellow solid (62mg, 10% of th.).

LC-MS (method 4): R_(t)=0.82 min; MS (ESIpos): m/z=405 (M+¹⁴)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=12.66 (s, 1H), 10.52 (s, 1H), 7.69 (m, 1H),7.61 (s, 1H), 7.58-7.48 (m, 2H), 7.36 (m, 1H), 7.30 (m, 1H), 5.00-4.84(m, 2H), 4.81 (s, 1H), 2.54 (s, 3H) ppm.

Example 322-Methyl-5-oxo-4-{3-[3-(trifluoromethyl)phenyl]-1H-indazol-5-yl]-1,4,5,7-tetrahydrofuro[3,4-b]-pyridine-3-carbonitrile

To a degassed solution of 120 mg (0.323 mmol)4-(3-bromo-1H-indazol-5-yl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carbonitrile(Example 24) and 73.7 mg (0.388 mmol) [3-(trifluoromethyl)phenyl]boronicacid in anhydrous 1,4-dioxane (4.8 ml) were added under argon atmosphere37.4 mg (0.032 mmol) tetrakis(triphenylphosphine)palladium(0) andaqueous sodium bicarbonate solution (2 M, 0.77 ml). The resultingmixture was stirred at 95° C. for 12 h. After cooling to roomtemperature and concentration under reduced pressure, the remainingsolid was dissolved in ethyl acetate (20 ml). The solution wassubsequently washed with water and brine, dried over sodium sulfate andconcentrated under reduced pressure. The crude product was purified bypreparative RP-HPLC (first run: acetonitrile/water gradient, finalmixture 95:5 v/v; second run: methanol/water isocratic 75:25 v/v) toyield the title compound as a white solid (6 mg, 4% of th.). LC-MS(method 6): R_(t)=2.14 min; MS (ESIpos): m/z=437 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ=13.47 (s, 1H), 10.20 (s, 1H), 8.29 (d, 1H),8.23 (s, 1H), 7.83 (s, 1H), 7.84-7.76 (m, 2H), 7.63 (d, 1H), 7.37 (d,1H), 4.90 (m, 2H), 4.76 (s, 1H), 2.13 (s, 3H) ppm.

The following compounds were prepared in analogy to the proceduredescribed for Example 19; purification was carried out by preparativesilica gel chromatography using a dichloromethane/methanol gradient.

Example Name/Structure (yield) Analytical data 334-(3-Methyl-1H-indazol-5-yl)-5-oxo-2-[4-(trifluoromethyl)phenyl]-1,4,5,7-tetra-hydrofuro[3,4-b]pyridine-3-carbonitrile  

  (6% of th.)¹ LC-MS (method 4): R_(t) = 0.93 min; m/z = 437 (M + H)⁺¹H-NMR (400 MHz, DMSO-d₆): δ = 12.64 (s, 1H), 10.49 (s, 1H), 7.94 (d,2H), 7.81 (d, 2H), 7.62 (s, 1H), 7.47 (d, 1H), 7.37 (d, 1H), 4.94 (m,2H), 4.82 (s, 1H), 2.54 (s, 3H) ppm. 344-(6-Fluoro-1H-indazol-5-yl)-5-oxo-2-[4-(trifluoromethyl)phenyl]-1,4,5,7-tetra-hydrofuro[3,4-b]pyridine-3-carbonitrile  

  (26% of th.) LC-MS (method 2): R_(t) = 1.04 min; m/z = 441 (M + H)⁺¹H-NMR (400 MHz, DMSO-d₆): δ = 13.17 (s, 1H), 10.57 (s, 1H), 8.11 (s,1H), 7.94 (m, 2H), 7.86-7.81 (m, 3H), 7.36 (d, 1H), 5.06 (s, 1H), 4.95(m, 2H) ppm. 35 2-(4-Chlorophenyl)-4-(6-fluoro-1H-indazol-5-yl)-5-oxo-1,4,5,7-tetrahydro-furo[3,4-b]pyridine-3-carbonitrile  

  (33% of th.) LC-MS (method 4): R_(t) = 0.88 min; m/z = 407 (M + H)⁺¹H-NMR (400 MHz, DMSO-d₆): δ = 13.16 (s, 1H), 10.48 (s, 1H), 8.10 (s,1H), 7.80 (d, 2H), 7.62 (m, 4H), 7.37 (d, 1H), 5.02 (s, 1H), 4.93 (m,2H) ppm. 36 4-(6-Fluoro-1H-indazol-5-yl)-2-(4-fluoro-phenyl)-5-oxo-1,4,5,7-tetrahydro- furo[3,4-b]pyridine-3-carbonitrile  

  (28% of th.) LC-MS (method 4): R_(t) = 0.82 min; m/z = 391 (M + H)⁺¹H-NMR (400 MHz, DMSO-d₆): δ = 13.15 (s, 1H), 10.45 (s, 1H), 8.10 (s,1H), 7.82 (d, 1H), 7.65 (m, 2H), 7.42- 7.34 (m, 3H), 5.02 (s, 1H), 4.93(m, 2H) ppm. ¹after further purification by preparative RP-HPLC [column:Sunfire C18, 5 μm, 19 mm × 150 mm; eluent: acetonitrile/water gradient,final mixture 70:30 v/v; flow rate: 25 ml/min; temperature: 30° C.; UVdetection: 210 nm].

The following compounds were prepared in analogy to the proceduredescribed for Example 16; purification was carried out by preparativeRP-HPLC using an acetonitrile/water+0.1% TFA gradient.

Example Name/Structure (yield) Analytical data 374-(6-Fluoro-1H-indazol-5-yl)-5-oxo-2-(trifluoromethyl)-1,4,5,7-tetrahydro- furo[3,4-b]pyridine-3-carbonitrile 

  (5% of th.) LC-MS (method 2): R_(t) = 0.86 min; m/z = 365 (M + H)⁺¹H-NMR (400 MHz, DMSO-d₆): δ = 13.20 (s, 1H), 11.10 (s, 1H), 8.11 (s,1H), 7.81 (d, 1H), 7.38 (d, 1H), 5.12 (s, 1H), 4.94 (m, 2H) ppm. 384-(6-Fluoro-3-methyl-1H-indazol-5-yl)-5-oxo-2-(trifluoromethyl)-1,4,5,7- tetra-hydrofuro[3,4-b]pyridine-3-carbonitrile  

  (10% of th.) LC-MS (method 4): R_(t) = 0.79 min; m/z = 379 (M + H)⁺¹H-NMR (400 MHz, DMSO-d₆): δ = 12.77 (s, 1H), 11.07 (s, 1H), 7.72 (d,1H), 7.28 (d, 1H), 5.11 (s, 1H), 4.94 (m, 2H), 2.50 (s, 3H) ppm.

Example 394-(3-Methyl-1H-indazol-5-yl)-5-oxo-2-(propan-2-yl)-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carbonitrile

A solution of 50 mg (0.312 mmol) 3-methyl-1H-indazole-5-carbaldehyde(Example 1A), 34 mg (0.312 mmol) 3-amino-4-methylpent-2-enenitrile [P.Stanetty et al., Monatshefte für Chemie 1999, 130, 441-450] and 59 mg(0.312 mmol) ethyl 4-(acetoxy)-3-oxobutanoate [preparation: U.S. Pat.No. 4,720,572 (Example 1)] in 1-propanol (1 ml) was stirred at refluxtemperature overnight. Then, concentrated hydrochloric acid (60 μl) andwater (175 μl) were added, and stirring was continued at 100° C. for 1h. After cooling to room temperature, the mixture was directly purifiedby preparative RP-HPLC (acetonitrile/water+0.1% TFA gradient) to yield50 mg (48% of th.) of the racemic title compound.

LC-MS (method 4): R_(t)=0.77 min; MS (ESIpos): m/z=335 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=12.62 (br. s, 1H), 9.83 (s, 1H), 7.49 (s,1H), 7.42 (d, 1H), 7.22 (d, 1H), 4.90 (dd, 2H), 4.61 (s, 1H), 3.02(sept, 1H), 2.48 (s, 3H), 1.20 (dd, 6H) ppm.

B. EVALUATION OF BIOLOGICAL ACTIVITY

Demonstration of the activity of the compounds of the present inventionmay be accomplished through in vitro, ex vivo, and in vivo assays thatare well known in the art. For example, to demonstrate the activity ofthe compounds of the present invention, the following assays may beused.

c-Met Receptor Tyrosine Kinase Activity Assay (NADH Read-Out):

Recombinant human c-Met protein (Invitrogen, Carlsbad, Calif., USA) isused. As substrate for the kinase reaction the peptide KKKSPGEYVNIEFG(JPT, Germany) is used. For the assay, 1 μL of a 51-fold concentratedsolution of the test compound in DMSO is pipetted into a white 384-wellmicrotiter plate (Greiner Bio-One, Frickenhausen, Germany). 25 μL of asolution of c-Met (final concentration 30 nM) and pyruvatekinase/lactate dehydrogenase (Roche Diagnostics, Mannheim, Germany;final concentration 8 mg/L) in assay buffer[3-(N-morpholino)propane-sulfonic acid (MOPS), 50 mM, pH 7; MgCl₂, 10mM; bovine serum albumin (BSA), 0.01%; Triton X 100, 0.01%; DTT, 2 mM]are added, and the mixture is incubated for 5 min at room temperature.Then, the kinase reaction is started by the addition of 25 μL of asolution of adenosine triphosphate (ATP, final concentration 30 μM),substrate (final concentration 100 μM), nicotinamide adeninedinucleotide (NADH, final concentration 50 μM) and dithiothreitol (DTT,final concentration 2 mM) in assay buffer, and the resulting mixture isincubated for a reaction time of 100 min at 32° C.

Subsequently, the amount of phosphorylated substrate is evaluated bymeasurement of the decrease of NADH fluorescence. Therefore, thefluorescence emissions at 465 nm after excitation at 340 nm is measuredin a fluorescence reader, e.g. Tecan Ultra (Tecan, Mannedorf,Switzerland). The data are normalised (enzyme reaction withoutinhibitor=0% inhibition; all other assay components but no enzyme=100%inhibition). Normally, test compounds are tested on the same microtiterplate at 9 different concentrations in the range of 10 μM to 1 nM (10μM, 3.1 μM, 1.0 μM, 0.3 μM, 0.1 μM, 0.03 μM, 0.01 μM, 0.003 μM, 0.001μM; dilution series prepared before the assay at the level of the51-fold concentrated stock solutions by serial 1:3 dilutions) induplicate for each concentration, and IC₅₀ values are calculated usingan inhouse software.

Compounds of the invention, when tested in this assay, demonstrated theability to inhibit c-Met tyrosine kinase activity at IC₅₀ values of lessthan 10 μM, preferably at less than 1 μM.

Some representative IC₅₀ values are listed in the table below:

Example No. IC₅₀ [μM]  2 0.014  8 0.11  18 0.015 22 0.009 25 0.016 360.019 38 0.020 39 0.014c-Met Receptor Tyrosine Kinase Homogeneous Time-Resolved FluorescenceAssay (Alternative Format):

The N-terminally His6-tagged recombinant kinase domain of the humanc-Met (amino acids 960-1390), expressed in insect cells (SF21) andpurified by Ni-NTA affinity chromatography and consecutive sizeexclusion chromatography (Superdex 200), is used. Alternatively,commercially available c-Met (Millipore) can be used. As substrate forthe kinase reaction, the biotinylated poly-Glu,Tyr (4:1) copolymer(#61GTOBLC, Cis Biointernational, Marcoule, France) is used.

For the assay, 50 mL of a 100-fold concentrated solution of the testcompound in DMSO is pipetted into a black low-volume 384-well microtiterplate (Greiner Bio-One, Frickenhausen, Germany). 2 μL of a solution ofc-Met in assay buffer [25 mM Hepes/NaOH, pH 7.5; 5 mM MgCl₂; 5 mM MnCl₂;2 mM dithiothreitol; 0.1% (v/v) Tween 20 (Sigma); 0.1% (w/v) bovineserum albumin] are added, and the mixture is incubated for 15 min at 22°C. to allow pre-binding of the test compound to the enzyme before thestart of the kinase reaction. Then, the kinase reaction is started bythe addition of 3 μL of a solution of adenosine triphosphate (ATP, 16.7μM; final concentration in the 5 μL assay volume is 10 μM) and substrate(2.27 μg/mL, final concentration in the 5 μL assay volume is 1.36μg/mL˜30 nM) in assay buffer, and the resulting mixture is incubated fora reaction time of 30 min at 22° C. The concentration of c-Met in theassay is adjusted depending on the activity of the enzyme lot and isappropriately chosen to have the assay in the linear range; typicalenzyme concentrations are in the range of about 0.03 nM (finalconcentration in the 5 μL assay volume). The reaction is stopped by theaddition of 5 μL of a solution of HTRF detection reagents [40 nMstreptavidine-XLent and 2.4 nM PT66-Eu-chelate, an europium-chelatelabelled anti-phosphotyrosine antibody (Perkin-Elmer)] in an aqueousEDTA solution [100 mM EDTA, 0.2% (w/v) bovine serum albumin in 50 mMHEPES/NaOH, pH 7.5].

The resulting mixture is incubated for 1 h at 22° C. to allow thebinding of the biotinylated phosphorylated peptide to thestreptavidine-XLent and the PT66-Eu-chelate. Subsequently, the amount ofphosphorylated substrate is evaluated by measurement of the resonanceenergy transfer from the PT66-Eu-chelate to the streptavidine-XLent.Therefore, the fluorescence emissions at 620 nm and 665 nm afterexcitation at 350 nm are measured in an HTRF reader, e.g. Rubystar (BMGLab-technologies, Offenburg, Germany) or Viewlux (Perkin-Elmer). Theratio of the emissions at 665 nm and at 622 nm is taken as the measurefor the amount of phosphorylated substrate. The data are normalised(enzyme reaction without inhibitor=0% inhibition; all other assaycomponents but no enzyme=100% inhibition). Normally, test compounds aretested on the same microtiter plate at 10 different concentrations inthe range of 20 μM to 1 nM (20 μM, 6.7 μM, 2.2 μM, 0.74 μM, 0.25 μM, 82nM, 27 nM, 9.2 nM, 3.1 nM and 1 nM; dilution series prepared before theassay at the level of the 100-fold concentrated stock solutions byserial 1:3 dilutions) in duplicate for each concentration, and IC₅₀values are calculated by a 4-parameter-fit using an inhouse software.

Compounds of the invention, when tested in this assay, demonstrated theability to inhibit c-Met tyrosine kinase activity at IC₅₀ values of lessthan 10 μM, preferably at less than 1 μM.

Some representative IC₅₀ values are listed in the table below:

Example No. IC₅₀ [μM]  2 0.001  7 0.028  8 0.25  16 0.007 18 0.002 310.002 38 0.020

Phospho-c-Met Assay:

This is a cell based, ELISA-like assay [Mesoscale Discovery (MSD),Gaithersburg, Md., USA] using MKN-45 tumor cells (gastric carcinoma,purchased from ATCC) without growth factor stimulation. The cells areplated in full growth media (10 000 cells/well) in 96-well plates on dayone. On day two, after a two-hour drug treatment in serum-free media,cells are washed and then lysed (60 μl/well using MSD recommended lysisbuffer) and frozen at −80° C. Also on day two, non-specificantibody-binding sites on the MSD phospho-Met plates are blocked withMSD Blocking Solution A overnight at 4° C. On day three, frozen lysatesare thawed on ice, and 25 μl of lysate is transferred to the MSDphospho-Met plate, for 1 hour with shaking, after washing once withTris-buffered saline+0.05% Tween 20 (TBST). After removing the unboundproteins, the Sulfa-TAG anti-Met antibody from MSD is added at a finalconcentration of 5 nM in antibody dilution buffer (following protocol ofMSD) to the plate for 1 hour with shaking. The plate is then washed withTBST buffer three times before adding 1×MSD Read Buffer. The plate isthen read on the MSD Discovery Workstation instrument. Raw data,including wells with 10 μM of a reference compound (minimum signal), andDMSO wells without any drug treatment (maximum signal), are entered intothe Analyze 5 program for IC₅₀ value determinations.

Cellular Phospho-c-Met Assay:

Human gastric adenocarcinoma cells (MKN45, purchased from ATCC) seededon 384-well microtiter plates (9000 cells/well) are incubated in 25 μlfull growth media for 24 h at 37° C. with 5% CO₂. On day two, after atwo-hour drug treatment in serum-reduced media containing 0.1% FCS,cells are washed and lysed. Lysates are transferred to BSA-blockedplates with prebound c-Met capture antibody [purchased from MesoscaleDiscovery (MSD), Gaithersburg, Md., USA] for 1 hour with shaking, afterwashing once with Tris-buffered saline+0.05% Tween 20 (TBST). Followingthe MSD protocol, the Sulfa-TAG anti-phospho-c-Met detection antibody isadded at a final concentration of 5 nM in antibody dilution buffer tothe plate for 1 hour with shaking at RT. After washing the wells withTris buffer, 1× reading buffer is added, and the plates are measured onthe Sector Imager 6000 (purchased from Mesoscale). IC₅₀ values arecalculated from dose-response curves using Marquardt-Levenberg-Fit.

In-Vitro Tumor Cell Proliferation Assay:

The adherent tumor cell proliferation assay used to test the compoundsof the present invention involves a read-out called Cell Titre-Glodeveloped by Promega [B. A. Cunningham, “A Growing Issue: CellProliferation Assays. Modern kits ease quantification of cell growth”,The Scientist 2001, 15 (13), 26; S. P. Crouch et al., “The use of ATPbioluminescence as a measure of cell proliferation and cytotoxicity”,Journal of Immunological Methods 1993, 160, 81-88]. Generation of aluminescent signal corresponds to the amount of ATP present, which isdirectly proportional to the number of metabolically active(proliferating) cells.

H460 cells (lung carcinoma, purchased from ATCC) are plated in 96-wellplates at 3000 cells/well in complete media with 10% fetal calf serumand incubated 24 hours at 37° C. Twenty-four hours after plating, testcompounds are added over a final concentration range of 10 nM to 20 μMin serial dilutions at a final DMSO concentration of 0.2%. Cells areincubated for 72 hours at 37° C. in complete growth media after additionof the test compound. On day 4, using a Promega Cell Titre-GloLuminescent® assay kit, the cells are lysed, and 100 μl ofsubstrate/buffer mixture is added to each well, mixed and incubated atroom temperature for 8 minutes. The samples are read on a luminometer tomeasure the amount of ATP present in the cell lysates from each well,which corresponds to the number of viable cells in that well. Valuesread at 24-hour incubation are subtracted as Day 0. For determination ofIC₅₀ values, a linear regression analysis can be used to determine thedrug concentration which results in a 50% inhibition of cellproliferation using this assay format. This protocol can be applied todifferent cell lines of interest, which include, but not limited to,CAKI-1, MNK-45, GTL-16, HCC2998, K562, H441, K812, MEG01, SUP15 andHCT116.

In-Vitro Clearance Determinations with Liver Microsomes:

Microsomal incubations are performed at 37° C. in a total volume of 1.5ml using a modified Janus® robotic system (Perkin-Elmer). The incubationmixtures contain 0.5 mg/ml microsomal protein, ˜1 μM substrate, 0.05 Mpotassium phosphate buffer (pH 7.4), 1 mM EDTA, 5 mM glucose-6-phosphateand 1.5 U/ml glucose-6-phosphate dehydroxygenase from LeuconostocMesenteroides. Although the reaction is started by adding NADP⁺ (finalconcentration 1 mM), FMO-activity is maintained. The final acetonitrile(ACN) concentration is ≦1%.

Aliquots of 125 μl are withdrawn from the incubation mixture after 2, 5,10, 20, 30 and 60 min or after 2, 10, 20, 30, 50, 70 and 90 min,depending on the metabolic stability of the compound, and are dispensedin a 96-well plate containing 250 μl ACN to stop the reaction. Aftercentrifugation, supernatants are analyzed by MSMS (typically API 2000 orAPI 3000).

Calculation of in-vitro clearance values (CL) from half-life data (t₁₁₂)in liver microsomes, reflecting substrate depletion, is performed usingthe following equation [J. B. Houston, Biochem. Pharmacol. 1994, 47 (9),1469-79; R. S. Obach et al., J. Pharmacol. Exp. Ther. 1997, 283 (1),46-58]:

CL _(intrinsic)′ [ml/(min·kg)]=(0.693/in vitro t_(1/2) [min])·(liverweight [g liver/kg body mass])·(microsomal protein [mg]/liver weight[g])/(microsomal protein [mg]/incubation volume ml]).

The CL_(blood) value is estimated using the non-restricted well-stirredmodel [K. S. Pang, M. Rowland, J. Pharmacokin. Biopharm. 1977, 5 (6),625-53]:

CL _(blood) well-stirred [L/(h·kg)]=(Q _(H) [L/(h·kg)]·CL _(intrinsic)′[L/(h·kg)])/(Q _(H) [L/(h·kg)]+CL _(intrinsic)′ [L/(h·kg)]).

Specific liver weights and hepatic blood flows (Q_(H)) are 32 g/kg bodymass and 4.2 L/(h·kg), respectively, for rats, and 21 g/kg body mass and1.32 L/(h·kg), respectively, for man. For both species, a specificmicrosomal protein content in the liver of 40 mg/g is assumed.Species-specific factors for the prediction of in-vivo clearance valuesfor other species are shown below:

male/female Mouse Mouse Rat Dog Cyno Man m f m/f m/f f m/f microsomal 4040 40 40 40 40 protein [mg]/ g liver liver [g]/ 50 43 32 39 30 21 kgbody weight liver blood 5.4 5.4 4.2 2.1 2.5 1.3 flow [L/(h · kg)]

F_(max) values (maximal possible bioavailability) are calculated usingthe formula:

F _(max) well-stirred [%]=[1−(CL _(blood) well-stirred [L/(h·kg)]/Q _(H)[L/(h·kg)])]·100.

In-Vitro Clearance Determinations with Hepatocytes:

Incubations with hepatocytes are performed at 37° C. in a total volumeof 1.5 ml using a modified Janus® robotic system (Perkin-Elmer). Theincubation mixtures contain 1 million viable cells/ml, ˜1 μM substrateand 0.05 M potassium phosphate buffer (pH 7.4). The final acetonitrile(ACN) concentration is ≦1%.

Aliquots of 125 μl are withdrawn from the incubation mixture after 2,10, 20, 30, 50, 70 and 90 min and typically dispensed in a 96-wellfilter plate (0.45 μm low-binding hydrophilic PTFE; Millipore,MultiScreen Solvinert), containing 250 μl ACN to stop the reaction.After centrifugation, filtrates are analyzed by MSMS (typically API 2000or API 3000).

Calculation of in-vitro clearance values (CL) from half-life data(t_(1/2)) in hepatocytes, reflecting substrate depletion, is performedusing the following equation [J. B. Houston, Biochem. Pharmacol. 1994,47 (9), 1469-79; R. S. Obach et al., J. Pharmacol. Exp. Ther. 1997, 283(1), 46-58]:

CL _(intrinic)′ [ml/(min·kg)]=(0.693/in vitro t_(1/2) [min])·(liverweight [g liver/kg body mass])·(cell number [1.1·10⁸]/liver weight[g])/(cell number [1·10⁶]/incubation volume [ml]).

The CL_(blood) value is estimated using the non-restricted well-stirredmodel [K. S. Pang, M. Rowland, J. Pharmacokin. Biopharm. 1977, 5 (6),625-53]:

CL _(blood) well-stirred [L/(h·kg)]=(Q _(H) [L/(h·kg)]·CL _(intrinsic)′[L/(h·kg)])/(Q _(H) [L/(h·kg)]+CL _(intinsic)′ [L/(h·kg)]).

Specific liver weights and hepatic blood flows (Q_(H)) are 32 g/kg bodymass and 4.2 L/(h·kg), respectively, for rats, 40 g/kg body mass and 2.1L/(h·kg) for dogs, and 21 g/kg body mass and 1.32 L/(h·kg) for man. Thecell number in the liver is supposed to be 110 million cells/g liver forall species used. Species-specific factors for the prediction of in-vivoclearance values for other species are shown below:

male/female Mouse Mouse Rat Dog Cyno Man m f m/f m/f f m/f cell number110 110 110 110 110 110 [·10⁶]/g liver liver [g]/ 50 43 32 39 30 21 kgbody weight liver blood 5.4 5.4 4.2 2.1 2.5 1.3 flow [L/(h · kg)]

F_(max) values (maximal possible bioavailability) are calculated usingthe formula:

F _(max) well-stirred [%]=[1−(CL_(blood) well-stirred [L/(h·kg)]/Q _(H)[L/(h·kg)])]·100.

Although the invention has been disclosed with reference to specificembodiments, it is apparent that other embodiments and variations of theinvention may be devised by others skilled in the art without departingfrom the true spirit and scope of the invention. The claims are intendedto be construed to include all such embodiments and equivalentvariations.

C. EXAMPLES RELATING TO PHARMACEUTICAL COMPOSITIONS

Pharmaceutical compositions according to the present invention can beillustrated as follows:

Sterile i.v. Solution:

A 5 mg/ml solution of the desired compound of this invention can be madeusing sterile, injectable water, and the pH is adjusted if necessary.The solution is diluted for administration to 1-2 mg/ml with sterile 5%dextrose and is administered as an i.v. infusion over about 60 minutes.

Lyophilized Powder for i.v. Administration:

A sterile preparation can be prepared with (i) 100-1000 mg of thedesired compound of this invention as a lyophilized powder, (ii) 32-327mg/ml sodium citrate, and (iii) 300-3000 mg Dextran 40. The formulationis reconstituted with sterile, injectable saline or 5% dextrose to aconcentration of 10 to 20 mg/ml, which is further diluted with saline or5% dextrose to 0.2 to 0.4 mg/ml, and is administered either as i.v.bolus or by i.v. infusion over 15-60 minutes.

Intramuscular Suspension:

The following solution or suspension can be prepared for intramuscularinjection:

50 mg/ml of the desired, water-insoluble compound of this invention; 5mg/ml sodium carboxymethylcellulose; 4 mg/mL TWEEN 80; 9 mg/ml sodiumchloride; 9 mg/ml benzyl alcohol.

Hard Shell Capsules:

A large number of unit capsules are prepared by filling standardtwo-piece hard galantine capsules each with 100 mg of powdered activeingredient, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesiumstearate.

Soft Gelatin Capsules:

A mixture of active ingredient in a digestible oil such as soybean oil,cottonseed oil or olive oil is prepared and injected by means of apositive displacement pump into molten gelatin to form soft gelatincapsules containing 100 mg of the active ingredient. The capsules arewashed and dried. The active ingredient can be dissolved in a mixture ofpolyethylene glycol, glycerin and sorbitol to prepare a water-misciblemedicine mix.

Tablets:

A large number of tablets are prepared by conventional procedures sothat the dosage unit is 100 mg of active ingredient, 0.2 mg of colloidalsilicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystallinecellulose, 11 mg of starch, and 98.8 mg of lactose. Appropriate aqueousand non-aqueous coatings may be applied to increase palatability,improve elegance and stability, or delay absorption.

1. A compound of formula (I)

wherein A is —C(═O)— or —S(═O)₂—, D is —CR^(6A)R^(6B)—, —O— or —NR⁷—,wherein R^(6A), R^(6B) and R⁷ are independently hydrogen or(C₁-C₄)-alkyl optionally substituted with hydroxy or up to three fluoroatoms, E is —CR^(8A)R^(8B)— or *—CR^(8A)R^(8B)—CR^(8C)R^(8D)—**,wherein * denotes the link to the dihydropyridine ring, ** denotes thelink to the D group, and R^(8A), R^(8B), R^(8C) and R^(8D) areindependently hydrogen, fluoro or (C₁-C₄)-alkyl optionally substitutedwith hydroxy, (C₁-C₄)-alkoxy, amino, mono-(C₁-C₄)-alkylamino ordi-(C₁-C₄)-alkylamino or up to three fluoro atoms, or R^(8A) and R^(8B)are joined and, taken together with the carbon atom to which they areattached, form a cyclopropyl or cyclobutyl ring, R¹ is selected from thegroup consisting of hydrogen, chloro, bromo, (C₁-C₆)-alkyl,(C₃-C₇)-cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to10-membered heteroaryl and benzo-1,4-dioxanyl, wherein (i) said(C₃-C₇)-cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl and 5- to10-membered heteroaryl are optionally substituted with one or twosubstituents independently selected from the group consisting of fluoro,chloro, bromo, difluoromethyl, trifluoromethyl, (C₁-C₄)-alkyl, oxo,hydroxy, difluoromethoxy, trifluoromethoxy, (C₁-C₄)-alkoxy, amino,mono-(C₁-C₄)-alkylamino, di-(C₁-C₄)-alkylamino, (C₃-C₆)-cycloalkyl and4- to 6-membered heterocycloalkyl, wherein the alkyl groups of said(C₁-C₄)-alkoxy, mono-(C₁-C₄)-alkylamino and di-(C₁-C₄)-alkylaminosubstituents in turn are optionally substituted with hydroxy or(C₁-C₄)-alkoxy, and (ii) said (C₁-C₆)-alkyl is optionally substitutedwith one, two or three substituents independently selected from thegroup consisting of fluoro, trifluoromethyl, hydroxy, (C₁-C₄)-alkoxy,amino, mono-(C₁-C₄)-alkylamino, di-(C₁-C₄)-alkylamino,(C₃-C₇)-cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl and 5- to10-membered heteroaryl, wherein said (C₃-C₇)-cycloalkyl, phenyl, 4- to7-membered heterocycloalkyl and 5- to 10-membered heteroarylsubstituents in turn are optionally substituted with one or two residuesindependently selected from the group consisting of fluoro, chloro,bromo, difluoromethyl, trifluoromethyl, (C₁-C₄)-alkyl, oxo, hydroxy,difluoromethoxy, trifluoromethoxy, (C₁-C₄)-alkoxy, amino,mono-(C₁-C₄)-alkylamino and di-(C₁-C₄)-alkylamino, or R¹ is a group ofthe formula NR^(9A)R^(9B) or —OR¹⁰, wherein R^(9A) and R^(9B) areindependently selected from the group consisting of hydrogen,(C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl and 4- to 7-membered heterocycloalkyl,wherein (i) said (C₃-C₇)-cycloalkyl and 4- to 7-memberedheterocycloalkyl are optionally substituted with one or two substituentsindependently selected from the group consisting of fluoro,difluoromethyl, trifluoromethyl, (C₁-C₄)-alkyl, oxo, hydroxy,difluoromethoxy, trifluoromethoxy, (C₁-C₄)-alkoxy, amino,mono-(C₁-C₄)-alkylamino and di-(C₁-C₄)-alkylamino, and (ii) said(C₁-C₆)-alkyl is optionally substituted with one, two or threesubstituents independently selected from the group consisting of fluoro,trifluoromethyl, hydroxy, (C₁-C₄)-alkoxy, amino,mono-(C₁-C₄)-alkylamino, di-(C₁-C₄)-alkylamino, (C₃-C₇)-cycloalkyl,phenyl, 4- to 7-membered heterocycloalkyl and 5- to 10-memberedheteroaryl, wherein said (C₃-C₇)-cycloalkyl, phenyl, 4- to 7-memberedheterocycloalkyl and 5- to 10-membered heteroaryl substituents in turnare optionally substituted with one or two residues independentlyselected from the group consisting of fluoro, chloro, bromo,difluoromethyl, trifluoromethyl, (C₁-C₄)-alkyl, oxo, hydroxy,difluoromethoxy, trifluoromethoxy, (C₁-C₄)-alkoxy, amino,mono-(C₁-C₄)-alkylamino and di-(C₁-C₄)-alkylamino, or R^(9A) and R^(9B)are joined and, taken together with the nitrogen atom to which they areattached, form a 4- to 7-membered heterocycloalkyl ring, which maycontain a second ring heteroatom selected from N, O and S, and which isoptionally substituted with one or two substituents independentlyselected from the group consisting of fluoro, (C₁-C₄)-alkyl, oxo,hydroxy, (C₁-C₄)-alkoxy, amino, mono-(C₁-C₄)-alkylamino,di-(C₁-C₄)-alkylamino and (C₃-C₆)-cycloalkyl, R¹⁰ is selected from thegroup consisting of (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl and 4- to7-membered heterocycloalkyl, wherein (i) said (C₃-C₇)-cycloalkyl and 4-to 7-membered heterocycloalkyl are optionally substituted with one ortwo substituents independently selected from the group consisting offluoro, difluoromethyl, trifluoromethyl, (C₁-C₄)-alkyl, oxo, hydroxy,difluoromethoxy, trifluoromethoxy, (C₁-C₄)-alkoxy, amino,mono-(C₁-C₄)-alkylamino and di-(C₁-C₄)-alkylamino, and (ii) said(C₁-C₆)-alkyl is optionally substituted with one, two or threesubstituents independently selected from the group consisting of fluoro,trifluoromethyl, hydroxy, (C₁-C₄)-alkoxy, amino,mono-(C₁-C₄)-alkylamino, di-(C₁-C₄)-alkylamino, (C₃-C₇)-cycloalkyl,phenyl, 4- to 7-membered heterocycloalkyl and 5- to 10-memberedheteroaryl, wherein said (C₃-C₇)-cycloalkyl, phenyl, 4- to 7-memberedheterocycloalkyl and 5- to 10-membered heteroaryl substituents in turnare optionally substituted with one or two residues independentlyselected from the group consisting of fluoro, chloro, bromo,difluoromethyl, trifluoromethyl, (C₁-C₄)-alkyl, oxo, hydroxy,difluoromethoxy, trifluoromethoxy, (C₁-C₄)-alkoxy, amino,mono-(C₁-C₄)-alkylamino and di-(C₁-C₄)-alkylamino, R² is hydrogen,fluoro, chloro or methyl, R³ is hydrogen, (C₁-C₄)-alkyl or cyclopropyl,R⁴ is cyano or aminocarbonyl, R⁵ is selected from the group consistingof (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl, phenyl and 5- or 6-memberedheteroaryl, wherein (i) said (C₃-C₇)-cycloalkyl, phenyl and 5- or6-membered heteroaryl are optionally substituted with one or twosubstituents independently selected from the group consisting of fluoro,chloro, bromo, cyano, difluoromethyl, trifluoromethyl, (C₁-C₄)-alkyl,hydroxy, difluoromethoxy, trifluoromethoxy, (C₁-C₄)-alkoxy, amino,mono-(C₁-C₄)-alkylamino and di-(C₁-C₄)-alkylamino, and (ii) said(C₁-C₆)-alkyl is optionally substituted with up to three fluoro atoms orwith one or two substituents independently selected from the groupconsisting of trifluoromethyl, hydroxy, (C₁-C₄)-alkoxy, amino,mono-(C₁-C₄)-alkylamino, di-(C₁-C₄)-alkylamino, (C₃-C₇)-cycloalkyl,phenyl, 4- to 7-membered heterocycloalkyl and 5- or 6-memberedheteroaryl, wherein the alkyl groups of said (C₁-C₄)-alkoxy,mono-(C₁-C₄)-alkylamino and di-(C₁-C₄)-alkylamino substituents in turnare optionally substituted with up to three fluoro atoms or with one ortwo residues independently selected from the group consisting oftrifluoromethyl, hydroxy, (C₁-C₄)-alkoxy, amino,mono-(C₁-C₄)-alkylamino, di-(C₁-C₄)-alkylamino and 4- to 7-memberedheterocycloalkyl, and wherein said (C₃-C₇)-cycloalkyl, phenyl, 4- to7-membered heterocycloalkyl and 5- or 6-membered heteroaryl groups inturn are optionally substituted with one or two residues independentlyselected from the group consisting of fluoro, chloro, cyano,trifluoromethyl, (C₁-C₄)-alkyl, oxo, hydroxy, (C₁-C₄)-alkoxy, amino,mono-(C₁-C₄)-alkylamino and di-(C₁-C₄)-alkylamino, or R⁵ is(C₁-C₄)-alkoxycarbonyl, aminocarbonyl, mono-(C₁-C₄)-alkylaminocarbonylor di-(C₁-C₄)-alkylaminocarbonyl, or R³ and R⁵ are joined and, takentogether with the nitrogen and the carbon atom to which they areattached, form a fused ring of the formula

wherein G is —CH₂—, —C(CH₃)₂—, —CH(CF₃)—, —O— or —NR¹¹—, wherein R¹¹ ishydrogen or (C₁-C₄)-alkyl, and R^(12A) and R^(12B) are independentlyhydrogen or fluoro, or R⁴ and R⁵ are joined and, taken together with thecarbon atoms to which they are attached, form a fused lactone or lactamering of the formula

wherein M is —O— or —NR¹³—, wherein R¹³ is hydrogen or (C₁-C₄)-alkyl, ora pharmaceutically acceptable salt thereof.
 2. The compound of formula(I) according to claim 1, wherein A is —C(═O)—, D is —CH₂—, —O—, —NH— or—N(CH₃)—, E is —CR^(8A)R^(8B)— or *—CR^(8A)R^(8B)—CH₂—**, wherein *denotes the link to the dihydropyridine ring, ** denotes the link to theD group, and R^(8A) and R^(8B) are independently hydrogen or methyl, orR^(8A) and R^(8B) are joined and, taken together with the carbon atom towhich they are attached, form a cyclopropyl ring, R¹ is selected fromthe group consisting of hydrogen, (C₁-C₆)-alkyl, (C₃-C₆)-cycloalkyl,phenyl, 4- to 6-membered heterocycloalkyl and 5- or 6-memberedheteroaryl, wherein (i) said (C₃-C₆)-cycloalkyl, phenyl, 4- to6-membered heterocycloalkyl and 5- or 6-membered heteroaryl areoptionally substituted with one or two substituents independentlyselected from the group consisting of fluoro, chloro, difluoromethyl,trifluoromethyl, (C₁-C₄)-alkyl, oxo, hydroxy, difluoromethoxy,trifluoromethoxy, (C₁-C₄)-alkoxy, amino, mono-(C₁-C₄)-alkylamino,di-(C₁-C₄)-alkylamino and 4- to 6-membered heterocycloalkyl, wherein thealkyl groups of said (C₁-C₄)-alkoxy, mono-(C₁-C₄)-alkylamino anddi-(C₁-C₄)-alkylamino substituents in turn are optionally substitutedwith hydroxy, methoxy or ethoxy, and (ii) said (C₁-C₆)-alkyl isoptionally substituted with one, two or three substituents independentlyselected from the group consisting of fluoro, trifluoromethyl, hydroxy,(C₁-C₄)-alkoxy, amino, mono-(C₁-C₄)-alkylamino, di-(C₁-C₄)-alkylamino,(C₃-C₆)-cycloalkyl, 4- to 6-membered heterocycloalkyl and 5- or6-membered heteroaryl, wherein said (C₃-C₆)-cycloalkyl, 4- to 6-memberedheterocycloalkyl and 5- or 6-membered heteroaryl substituents in turnare optionally substituted with one or two residues independentlyselected from the group consisting of fluoro, chloro, difluoromethyl,trifluoromethyl, (C₁-C₄)-alkyl, oxo, hydroxy, (C₁-C₄)-alkoxy, amino,mono-(C₁-C₄)-alkylamino and di-(C₁-C₄)-alkylamino, or R¹ is a group ofthe formula NR^(9A)R^(9B) or —OR¹⁰, wherein R^(9A) is hydrogen or(C₁-C₄)-alkyl optionally substituted with one or two substituentsindependently selected from the group consisting of hydroxy,(C₁-C₄)-alkoxy, amino, mono-(C₁-C₄)-alkylamino anddi-(C₁-C₄)-alkylamino, R^(9B) is selected from the group consisting ofhydrogen, (C₁-C₆)-alkyl, (C₃-C₆)-cycloalkyl and 4- to 6-memberedheterocycloalkyl, wherein (i) said (C₃-C₆)-cycloalkyl and 4- to6-membered heterocycloalkyl are optionally substituted with one or twosubstituents independently selected from the group consisting of fluoro,difluoromethyl, trifluoromethyl, (C₁-C₄)-alkyl, oxo, hydroxy,(C₁-C₄)-alkoxy, amino, mono-(C₁-C₄)-alkylamino anddi-(C₁-C₄)-alkylamino, and (ii) said (C₁-C₆)-alkyl is optionallysubstituted with one, two or three substituents independently selectedfrom the group consisting of fluoro, trifluoromethyl, hydroxy,(C₁-C₄)-alkoxy, amino, mono-(C₁-C₄)-alkylamino, di-(C₁-C₄)-alkylamino,(C₃-C₆)-cycloalkyl, 4- to 6-membered heterocycloalkyl and 5- or6-membered heteroaryl, wherein said (C₃-C₆)-cycloalkyl, 4- to 6-memberedheterocycloalkyl and 5- or 6-membered heteroaryl substituents in turnare optionally substituted with one or two residues independentlyselected from the group consisting of fluoro, chloro, difluoromethyl,trifluoromethyl, (C₁-C₄)-alkyl, oxo, hydroxy, (C₁-C₄)-alkoxy, amino,mono-(C₁-C₄)-alkylamino and di-(C₁-C₄)-alkylamino, or R^(9A) and R^(9B)are joined and, taken together with the nitrogen atom to which they areattached, form a 4- to 6-membered heterocycloalkyl ring, which maycontain a second ring heteroatom selected from N and O, and which isoptionally substituted with one or two substituents independentlyselected from the group consisting of fluoro, (C₁-C₄)-alkyl, oxo,hydroxy, (C₁-C₄)-alkoxy, amino, mono-(C₁-C₄)-alkylamino anddi-(C₁-C₄)-alkylamino, R¹⁰ is selected from the group consisting of(C₁-C₆)-alkyl, (C₃-C₆)-cycloalkyl and 4- to 6-membered heterocycloalkyl,wherein (i) said (C₃-C₆)-cycloalkyl and 4- to 6-memberedheterocycloalkyl are optionally substituted with one or two substituentsindependently selected from the group consisting of fluoro,difluoromethyl, trifluoromethyl, (C₁-C₄)-alkyl, oxo, hydroxy,(C₁-C₄)-alkoxy, amino, mono-(C₁-C₄)-alkylamino anddi-(C₁-C₄)-alkylamino, and (ii) said (C₁-C₆)-alkyl is optionallysubstituted with one, two or three substituents independently selectedfrom the group consisting of fluoro, trifluoromethyl, hydroxy,(C₁-C₄)-alkoxy, amino, mono-(C₁-C₄)-alkylamino, di-(C₁-C₄)-alkylamino,(C₃-C₆)-cycloalkyl, 4- to 6-membered heterocycloalkyl and 5- or6-membered heteroaryl, wherein said (C₃-C₆)-cycloalkyl, 4- to 6-memberedheterocycloalkyl and 5- or 6-membered heteroaryl substituents in turnare optionally substituted with one or two residues independentlyselected from the group consisting of fluoro, chloro, difluoromethyl,trifluoromethyl, (C₁-C₄)-alkyl, oxo, hydroxy, (C₁-C₄)-alkoxy, amino,mono-(C₁-C₄)-alkylamino and di-(C₁-C₄)-alkylamino, R² is hydrogen orfluoro, R³ is hydrogen or (C₁-C₄)-alkyl, R⁴ is cyano, R⁵ is selectedfrom the group consisting of (C₁-C₄)-alkyl, cyclopropyl, phenyl and 5-or 6-membered heteroaryl, wherein (i) said cyclopropyl is optionallysubstituted with one or two substituents independently selected from thegroup consisting of fluoro, trifluoromethyl and methyl, (ii) said phenyland 5- or 6-membered heteroaryl are optionally substituted with one ortwo substituents independently selected from the group consisting offluoro, chloro, cyano, difluoromethyl, trifluoromethyl, (C₁-C₄)-alkyland (C₁-C₄)-alkoxy, and (iii) said (C₁-C₄)-alkyl is optionallysubstituted with up to three fluoro atoms or with one or twosubstituents independently selected from the group consisting of(C₁-C₄)-alkoxy, amino, mono-(C₁-C₄)-alkylamino, di-(C₁-C₄)-alkylamino,(C₃-C₆)-cycloalkyl, phenyl, 4- to 6-membered heterocycloalkyl and5-membered heteroaryl, wherein the alkyl groups of said (C₁-C₄)-alkoxy,mono-(C₁-C₄)-alkylamino and di-(C₁-C₄)-alkylamino substituents in turnare optionally substituted with up to three fluoro atoms or with one ortwo residues independently selected from the group consisting of(C₁-C₄)-alkoxy, amino, mono-(C₁-C₄)-alkylamino, di-(C₁-C₄)-alkylaminoand 4- to 6-membered heterocycloalkyl, and wherein said(C₃-C₆)-cycloalkyl, phenyl, 4- to 6-membered heterocycloalkyl and5-membered heteroaryl groups in turn are optionally substituted with oneor two residues independently selected from the group consisting offluoro, chloro, cyano, trifluoromethyl, (C₁-C₄)-alkyl, oxo,(C₁-C₄)-alkoxy, amino, mono-(C₁-C₄)-alkylamino anddi-(C₁-C₄)-alkylamino, or R³ and R⁵ are joined and, taken together withthe nitrogen and the carbon atom to which they are attached, form afused ring of the formula

wherein R^(12A) and R^(12B) are independently hydrogen or fluoro, or R⁴and R⁵ are joined and, taken together with the carbon atoms to whichthey are attached, form a fused lactone ring of the formula

or a pharmaceutically acceptable salt thereof.
 3. The compound offormula (I) according to claim 1, wherein A is —C(═O)—, D is —O—, E is—CH₂—, —CH(CH₃)— or —C(CH₃)₂—, R¹ is selected from the group consistingof hydrogen, (C₁-C₄)-alkyl, phenyl and 5- or 6-membered heteroaryl,wherein (i) said phenyl and 5- or 6-membered heteroaryl are optionallysubstituted with one or two substituents independently selected from thegroup consisting of fluoro, chloro, difluoromethyl, trifluoromethyl,(C₁-C₃)-alkyl, (C₁-C₃)-alkoxy, amino, mono-(C_(r) C₃)-alkylamino,di-(C₁-C₃)-alkylamino and 4- to 6-membered heterocycloalkyl, wherein thealkyl groups of said (C₁-C₃)-alkoxy, mono-(C₁-C₃)-alkylamino anddi-(C₁-C₃)-alkylamino substituents in turn are optionally substitutedwith methoxy or ethoxy, and (ii) said (C₁-C₄)-alkyl is optionallysubstituted with up to three fluoro atoms or with one or twosubstituents independently selected from the group consisting of(C₁-C₃)-alkoxy, amino, mono-(C₁-C₃)-alkylamino, di-(C₁-C₃)-alkylaminoand 4- to 6-membered heterocycloalkyl, wherein said 4- to 6-memberedheterocycloalkyl substituent in turn is optionally substituted with oneor two residues independently selected from the group consisting offluoro, trifluoromethyl, methyl, ethyl, oxo, methoxy, ethoxy, amino,methylamino, ethylamino, dimethylamino and diethylamino, or R¹ is agroup of the formula NR^(9A)R^(9B) or —OR¹⁰, wherein R^(9A) is hydrogenor (C₁-C₄)-alkyl optionally substituted with hydroxy, methoxy, ethoxy,amino, methylamino, ethylamino, dimethylamino or diethylamino, R^(9B) ishydrogen or (C₁-C₄)-alkyl optionally substituted with up to three fluoroatoms or with one or two substituents independently selected from thegroup consisting of hydroxy, (C₁-C₃)-alkoxy, amino,mono-(C₁-C₃)-alkylamino, di-(C₁-C₃)-alkylamino and 4- to 6-memberedheterocycloalkyl, wherein said 4- to 6-membered heterocycloalkylsubstituent in turn is optionally substituted with one or two residuesindependently selected from the group consisting of fluoro,trifluoromethyl, methyl, ethyl, oxo, methoxy, ethoxy, amino,methylamino, ethylamino, dimethylamino and diethylamino, or R^(9A) andR^(9B) are joined and, taken together with the nitrogen atom to whichthey are attached, form a 4- to 6-membered heterocycloalkyl ring, whichmay contain a second ring heteroatom selected from N and O, and which isoptionally substituted with one or two substituents independentlyselected from the group consisting of fluoro, methyl, ethyl, oxo,methoxy, ethoxy, amino, methylamino, ethylamino, dimethylamino anddiethylamino, R¹⁰ is (C₁-C₄)-alkyl optionally substituted with up tothree fluoro atoms or with one or two substituents independentlyselected from the group consisting of hydroxy, (C₁-C₃)-alkoxy, amino,mono-(C₁-C₃)-alkylamino, di-(C₁-C₃)-alkylamino and 4- to 6-memberedheterocycloalkyl, wherein said 4- to 6-membered heterocycloalkylsubstituent in turn is optionally substituted with one or two residuesindependently selected from the group consisting of fluoro,trifluoromethyl, methyl, ethyl, oxo, methoxy, ethoxy, amino,methylamino, ethylamino, dimethylamino and diethylamino, R² is hydrogenor fluoro, R³ is hydrogen or methyl, R⁴ is cyano, and R⁵ is selectedfrom the group consisting of (C₁-C₄)-alkyl, phenyl, pyridyl,pyrimidinyl, oxazolyl and isoxazolyl, wherein (i) said phenyl, pyridyl,pyrimidinyl, oxazolyl and isoxazolyl are optionally substituted with oneor two substituents independently selected from the group consisting offluoro, chloro, difluoromethyl, trifluoromethyl, methyl, ethyl, methoxyand ethoxy, and (ii) said (C₁-C₄)-alkyl is optionally substituted withup to three fluoro atoms or with a substituent selected from the groupconsisting of (C₁-C₃)-alkoxy, amino, mono-(C₁-C₃)-alkylamino,di-(C₁-C₃)-alkylamino, phenyl, 4- to 6-membered heterocycloalkyl and5-membered heteroaryl, wherein said phenyl and 5-membered heteroarylsubstituents in turn are optionally substituted with one or two residuesindependently selected from the group consisting of fluoro, chloro,trifluoromethyl, methyl, ethyl and amino, and wherein the alkyl groupsof said (C₁-C₃)-alkoxy, mono-(C₁-C₃)-alkylamino anddi-(C₁-C₃)-alkylamino substituents in turn are optionally substitutedwith up to three fluoro atoms or with a residue selected from the groupconsisting of methoxy, ethoxy, amino, methylamino, ethylamino,dimethylamino, diethylamino, azetidino, pyrrolidino, piperidino,piperazino and morpholino, and wherein said 4- to 6-memberedheterocycloalkyl substituent as well as said azetidino, pyrrolidino,piperidino, piperazino and morpholino groups in turn are optionallysubstituted with one or two residues independently selected from thegroup consisting of fluoro, methyl, ethyl and oxo, or a pharmaceuticallyacceptable salt, hydrate and/or solvate thereof.
 4. The compound offormula (I) according to claim 1, wherein A is —C(═O)—, D is —O—, E is—CH₂—, R¹ is hydrogen, methyl or ethyl, R² is hydrogen or fluoro, R³ ishydrogen or methyl, R⁴ is cyano, and R⁵ is (C₁-C₄)-alkyl optionallysubstituted with methoxy, ethoxy or up to three fluoro atoms, or isphenyl optionally substituted with one or two substituents independentlyselected from the group consisting of fluoro, chloro, methyl andtrifluoromethyl, or a pharmaceutically acceptable salt thereof.
 5. Aprocess for preparing a compound of formula (I) as defined in claim 1,wherein R³ is hydrogen, characterized in that an indazolyl aldehyde offormula (II)

wherein R¹ and R² have the meanings indicated in claim 1 claims 1, isreacted either [A] with a compound of formula (III)

or a sodium enolate thereof, wherein R⁴ and R⁵ have the meaningsindicated in claim 1, in the presence of an acid, an acid/basecombination and/or a dehydrating agent to give a compound of formula(IV)

wherein R¹, R², R⁴ and R⁵ have the meanings described above, and thelatter is then condensed with a compound of formula (V)

wherein A, D and E have the meanings indicated in claim 1, in thepresence of an ammonia source such as ammonium acetate to give thecompound of formula (I-A)

wherein A, D, E, R¹, R², R⁴ and R⁵ have the meanings described above, or[B] with a compound of formula (V)

wherein A, D and E have the meanings indicated in claim 1, optionally inthe presence of a base and/or a dehydrating agent to yield a compound offormula (VI)

wherein A, D, E, R¹ and R² have the meanings described above, and thelatter is then condensed with a compound of formula (VII)

wherein R⁴ and R⁵ have the meanings indicated in claim 1, in thepresence of an acid to give the compound of formula (I-A)

wherein A, D, E, R¹, R², R⁴ and R⁵ have the meanings described above,optionally followed, where appropriate, by (i) separating the compounds(I-A) into their respective enantiomers and/or diastereomers, and/or(ii) converting the compounds (I-A) into their respective salts bytreatment with the corresponding solvents and/or acids or bases. 6.(canceled)
 7. (canceled)
 8. (canceled)
 9. A pharmaceutical compositioncomprising a compound as defined in claim 1, and a pharmaceuticallyacceptable excipient.
 10. The pharmaceutical composition of claim 9further comprising one or more additional therapeutic agents.
 11. Thepharmaceutical composition of claim 10, wherein the additionaltherapeutic agent is an anti-tumor agent.
 12. (canceled)
 13. A method oftreating or preventing a cell proliferative disorder in a mammal,comprising administering to a mammal in need thereof a therapeuticallyeffective amount of one or more compounds as defined in claim
 1. 14. Themethod of claim 13, wherein the cell proliferative disorder is cancer.15. The method of claim 14, wherein the cancer is a cancer of thebreast, respiratory tract, brain, reproductive organs, digestive tract,urinary tract, eye, liver, skin, head or neck, thyroid, parathyroid, ora distant metastasis of a solid tumor.
 16. The method of claim 14,wherein the compound as defined in claim 1 is administered inconjunction with surgery or radiation therapy.
 17. A method of treatingor preventing a cell proliferative disorder in a mammal, comprisingadministering to a mammal in need thereof a therapeutically effectiveamount of a pharmaceutical composition as defined in claim
 9. 18. Themethod of claim 17, wherein the cell proliferative disorder is cancer.19. The method of claim 18, wherein the cancer is a cancer of thebreast, respiratory tract, brain, reproductive organs, digestive tract,urinary tract, eye, liver, skin, head or neck, thyroid, parathyroid, ora distant metastasis of a solid tumor.
 20. The method of claim 18,wherein the pharmaceutical composition as defined in claim 9 isadministered in conjunction with surgery or radiation therapy.